Trifluoromethoxylation of arenes via intramolecular trifluoromethoxy group migration

ABSTRACT

The present invention provides a process of producing a trifluoromethoxylated aryl or trifluoromethoxylated heteroaryl having the structure: 
     
       
         
         
             
             
         
       
     
     wherein
 
A is an aryl or heteroaryl, each with or without subsutitution; and
 
R 1  is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl) 2 , —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl); —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl), comprising:
 
(a) reacting a compound having the structure:
 
     
       
         
         
             
             
         
       
     
     with a trifluoromethylating agent in the presence of a base in a first suitable solvent under conditions to produce a compound having the structure: 
     
       
         
         
             
             
         
       
     
     and
 
(b) maintaining the compound produced in step (a) in a second suitable solvent under conditions sufficient to produce the trifluoromethoxylated aryl or trifluormethoxylated heteroaryl having the structure:

This application claims priority of U.S. Provisional Application Nos.62/192,789, filed Jul. 15, 2015; 62/192,462, filed Jul. 14, 2015;62/063,246, filed Oct. 13, 2014; and 62/062,508, filed Oct. 10, 2014,the contents of each of which are hereby incorporated by reference.

Throughout this application various publications are referenced. Thedisclosures of these documents in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this invention pertains.

BACKGROUND OF THE INVENTION

Fluorine atoms are often introduced into organic molecules to enhancetheir pharmacological properties such as solubility, metabolic andoxidative stability, lipophilicity, and bioavailability.^([1]) Among thefluorine containing functional groups, the trifluoromethoxy group (OCF₃)is of current interest because of its unique structural and electronicproperties, which can be useful in material, agricultural, andpharmaceutical science.^([2]) For example, one of the distinctstructural features of trifluoromethoxylated arenes (Ar—OCF₃) is thatthe OCF₃ bond is orthogonal to the aryl ring.^([3,1b]) As a result, lonepair electrons on oxygen only weakly delocalize into the ring, whichrenders OCF₃ an electron withdrawing group. In addition, the OCF₃ grouphas one of the highest lipophilicity values (π_(x)=1.04) compared to theCF₃ (π_(x)=0.88), CH₃ (π_(x)=0.52), F (π_(x)=0.14), and OCH₃(π_(x)=−0.02) groups.^([4]) Compounds with higher lipophilicity showenhancement in their in vivo uptake and transport in biological systems.Indeed, many OCF₃ containing pharmaceuticals and agrochemicals showenhanced effectiveness often coupled with diminished side-effects (FIG.1).^([2a,2b,5])

Despite the intriguing properties of the OCF₃ group, introduction ofthis functional group into organic molecules remains a challenge. Only ahandful of transformations have been developed over the last few decadesand most of them either suffer from poor substrate scope or require theuse of highly toxic and/or thermally unstable reagents. A pioneeringstudy by Yagupolskii and coworkers in 1955 led to the development of atwo-step chlorination/chlorine-fluorine exchange protocol for thesynthesis of simple aryl trifluoromethyl ethers.^([6]) In 1964, Sheppardreported an alternative approach involving reactions of aromatic oraliphatic alcohols with fluorophosgene followed by deoxyfluorinationwith tetrafluorosulfur (SF₄).^([7]) About thirty years later, Hiyamasynthesized aryl trifluoromethyl ethers via formation ofdithiocarbonates followed by oxidative fluorodesulfurization.^([8])Electrophilic trifluormethylations of alcohols and phenols have alsobeen developed. Employing thermally labile O-trifluoromethyldibenzylfuranium salts, Umemoto and coworkers successfully trifluoro-methylatedphenols to form aryl trifluoromethyl ethers.^([9]) An elegant directtrifluoromethylation of aliphatic alcohols using bench stable reagentwas reported by Togni and coworkers.^([10]) However, poor yields wereobtained for phenolic substrates due to the competingC-trifluoromethylation.^([11]) Most recently, a directtrifluoro-methoxylation of benzene employing toxic gaseoustrifluoromethyl perfluorite^([12a-b]), and a transition metal-mediatedtrifluoro-methoxylation of aryl stannanes as well as aryl boronic acidsutilizing thermally labile tris(dimethylamino)sulfoniumtrifluoro-methoxide have been developed.^([2b]) However, most of theseapproaches either suffer from poor substrate scope or require use ofhighly toxic and/or thermally labile reagents. As a result, many ofOCF₃-containing building blocks are prohibitively expensive (FIG. 1C).

SUMMARY OF THE INVENTION

The present invention provides a process of producing a compound havingthe structure:

wherein

A is an aryl or heteroaryl, each with or without subsutitution; and

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl), comprising:

(a) reacting a compound having the structure:

with a trifluoromethylating agent in the presence of a base in a firstsuitable solvent under conditions sufficient to produce the compoundhaving the structure:

The present invention also provides a process of producing atrifluoromethoxylated aryl or trifluoromethoxylated heteroaryl havingthe structure:

wherein

A is an aryl or heteroaryl, each with or without subsutitution; and

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl), comprising:

(b) maintaining the compound having the structure:

in a second suitable solvent under conditions sufficient to produce thetrifluoromethoxylated aryl or trifluormethoxylated heteroaryl having thestructure:

The present invention further provides a process of producing atrifluoromethoxylated aryl or trifluoromethoxylated heteroaryl havingthe structure:

wherein

A is an aryl or heteroaryl, each with or without subsutitution; and

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl), comprising:

(a) reacting a compound having the structure:

with a trifluoromethylating agent in the presence of a base in a firstsuitable solvent under conditions to produce a compound having thestructure:

and

(b) maintaining the compound produced in step (a) in a second suitablesolvent under conditions sufficient to produce the trifluoromethoxylatedaryl or trifluormethoxylated heteroaryl having the structure:

The present invention further provides a process of producing atrifluoromethoxylated aryl or trifluoromethoxylated heteroaryl havingthe structure:

wherein

A is an aryl or heteroaryl, each with or without subsutitution; and

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl), comprising:

(a) reacting a compound having the structure:

with a trifluoromethylating agent in a first suitable solvent underconditions to produce a compound having the structure:

and

(b) maintaining the compound produced in step (a) in the first suitablesolvent under conditions sufficient to produce the trifluoromethoxylatedaryl or trifluormethoxylated heteroaryl having the structure:

The present invention also provides a compound having the structure:

wherein

A is an aryl or heteroaryl, each with or without subsutitution; and

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl).

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A. Examples of OCF₃-bearing pharmaceuticals.

FIG. 1B. Examples of OCF₃-bearing agrochemicals.

FIG. 1C. Examples of OCF₃-bearing building blocks.

FIG. 2. Compounds 9a-9y. Cited yields and isomeric ratios are ofisolated material by column chromatography. ^(a)RT→50° C. in CH₂Cl₂.^(b)4° C. in CH₂Cl₂ (0.01 M). ^(c)Following the O-trifluoromethylationreaction in CH₂Cl₂ at RT, the reaction mixture was concentrated, theresidue was dissolved in MeNO₂, and the resulting mixture was heated.^(d)120° C. ^(e)80° C. ^(f)60° C.

FIG. 3. Compounds 11a-11e. Cited yields are of isolated material bycolumn chromatography. ^(a)Following the O-trifluoromethylation reactionin CH₂Cl₂ at RT, the reaction mixture was concentrated, the residue wasdissolved in MeNO₂, and the resulting mixture was heated at 80° C.^(b)CH₂Cl₂ (0.01 M). ^(c)RT→50° C. in CH₂Cl₂ (0.03 M). ^(d)RT→50° C. inCH₂Cl₂.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process of producing a compound havingthe structure:

wherein

A is an aryl or heteroaryl, each with or without subsutitution; and

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl),

comprising:

(a) reacting a compound having the structure:

with a trifluoromethylating agent in the presence of a base in a firstsuitable solvent under conditions sufficient to produce the compoundhaving the structure:

In some embodiments, the first suitable solvent is chloroform,dichloromethane, nitromethane, dimethylforamide, diethyl ether,tetrahydrofuran, dioxane, dichloroethane, or hexane.

In some embodiments, the first suitable solvent is degassed prior touse.

In some embodiments, step (a) is performed under an inert atmosphere.

In some embodiments, step (a) is carried out at room temperature.

In some embodiments, in step (a) the molar ratio of the compound to thetrifluormethylation agent is 1:1 to 1:2.

In some embodiments, in step (a) the molar ratio of the compound to thetrifluormethylation agent is 1:1.2.

In some embodiments, the trifluormethylating agent is Togni reagent I orTogni reagent II.

In some embodiments, the base is cesium carbonate or sodium hydride.

In some embodiments, a catalytic amount of the base is used.

In some embodiments, in step (a) the compound is reacted for 5-24 hours.In some embodiments, in step (a) the compound is reacted for about 15hours.

In some embodiments of step (a), A is a phenyl or pyridine. In someembodiments of step (a), A is a furan, thiophene, pyrrole, thiazole,imidazole, pyrazole, isooxazole, isothiazole, naphthalene, anthracene,pyrimidine, pyrazine, pyridazine, indole, indoline, benzofuran,benzothiophene, or quinolone.

In some embodiments, the compound produced in step (a) has thestructure:

wherein

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl); and R₂, R₃,R₄ and R₅ is each independently —H, halogen, —CN, —CF₃, —OCF₃, -(alkyl),-(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH₂, —NH-(alkyl),—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —CO₂-(alkyl),—CO₂-(alkenyl), —CO₂-(alkynyl)-CO₂-(aryl), —C(—CO₂-(heteroaryl),—C(O)NH-(alkyl), —C(O)NH-(alkenyl), —C(O)NH-(alkynyl) —C(O)NH-(aryl),—C(O)NH-(heteroaryl), —C(O)N(alkyl)₂, —OH, —OAc, —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), pyridine, furan,thiophene, pyrrole, thiazole, imidazole, pyrazole, isooxazole,isothiazole, naphthalene, anthracene, pyrimidine, pyrazine, pyridazine,indole, indoline, benzofuran, benzothiophene, or quinolone.

In some embodiments of the above compound R₂, R₃, R₄ and R₅ is each,independently, —H, halogen, —CN, —CF₃, —OCF₃, -(alkyl), -(alkenyl),-(alkynyl), -(aryl), -(heteroaryl), —NH₂, —NH-(alkyl), —NH-(alkenyl),—NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —CO₂-(alkyl),—CO₂-(alkenyl), —CO₂-(alkynyl)-CO₂-(aryl), —C(—CO₂-(heteroaryl),—C(O)NH-(alkyl), —C(O)NH-(alkenyl), —C(O)NH-(alkynyl) —C(O)NH-(aryl),—C(O)NH-(heteroaryl), —C(O)N(alkyl)₂, —OH, —OAc, —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), pyridine, furan,thiophene, pyrrole, thiazole, imidazole, pyrazole, isooxazole,isothiazole, naphthalene, anthracene, pyrimidine, pyrazine, pyridazine,indole, indoline, benzofuran, benzothiophene, quinolone, pyrazoline,triazole, benzimidazole, benzotriazole, azaindole, or purine.

In some embodiments of the above compound R₂, R₃, R₄ and R₅ is each,independently, —H, pyrazoline, triazole, benzimidazole, benzotriazole,azaindole, or purine.

In some embodiments, the compound produced in step (a) has thestructure:

wherein

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl); and R₂, R₃,R₄ and R₅ is each independently —H, halogen, —CN, —CF₃, —OCF₃, -(alkyl),-(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH₂, —NH-(alkyl),—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —CO₂-(alkyl),—CO₂-(alkenyl), —CO₂-(alkynyl)-CO₂-(aryl), —C(—CO₂-(heteroaryl),—C(O)NH-(alkyl), —C(O)NH-(alkenyl), —C(O)NH-(alkynyl) —C(O)NH-(aryl),—C(O)NH-(heteroaryl), —C(O)N(alkyl)₂, —OH, —OAc, —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), pyridine, furan,thiophene, pyrrole, thiazole, imidazole, pyrazole, isooxazole,isothiazole, naphthalene, anthracene, pyrimidine, pyrazine, pyridazine,indole, indoline, benzofuran, benzothiophene, or quinolone.

In some embodiments, the compound produced in step (a) has thestructure:

wherein

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl); and

R₂, R₃ and R₅ is each independently —H, halogen, —CN, —CF₃, —OCF₃,-(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH₂,—NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl),—CO₂-(alkyl), —CO₂-(alkenyl), —CO₂-(alkynyl)-CO₂-(aryl),—C(—CO₂-(heteroaryl), —C(O)NH-(alkyl), —C(O)NH-(alkenyl),—C(O)NH-(alkynyl) —C(O)NH-(aryl), —C(O)NH-(heteroaryl), —C(O)N(alkyl)₂,—OH, —OAc, —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl),—O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl),—S-(heteroaryl), pyridine, furan, thiophene, pyrrole, thiazole,imidazole, pyrazole, isooxazole, isothiazole, naphthalene, anthracene,pyrimidine, pyrazine, pyridazine, indole, indoline, benzofuran,benzothiophene, or quinolone.

In some embodiments, the compound produced in step (a) has thestructure:

wherein

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl); and

R₃, R₄ and R₅ is each independently —H, halogen, —CN, —CF₃, —OCF₃,-(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH₂,—NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl),—CO₂-(alkyl), —CO₂-(alkenyl), —CO₂-(alkynyl)-CO₂-(aryl),—C(—CO₂-(heteroaryl), —C(O)NH-(alkyl), —C(O)NH-(alkenyl),—C(O)NH-(alkynyl) —C(O)NH-(aryl), —C(O)NH-(heteroaryl), —C(O)N(alkyl)₂,—OH, —OAc, —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl),—O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl),—S-(heteroaryl), pyridine, furan, thiophene, pyrrole, thiazole,imidazole, pyrazole, isooxazole, isothiazole, naphthalene, anthracene,pyrimidine, pyrazine, pyridazine, indole, indoline, benzofuran,benzothiophene, quinolone, pyrazoline, triazole, benzimidazole,benzotriazole, azaindole, or purine.

The present invention also provides a process of producing atrifluoromethoxylated aryl or trifluoromethoxylated heteroaryl havingthe structure:

wherein

A is an aryl or heteroaryl, each with or without subsutitution; and

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl), comprising:

(b) maintaining the compound having the structure:

in a second suitable solvent under conditions sufficient to produce thetrifluoromethoxylated aryl or trifluormethoxylated heteroaryl having thestructure:

In some embodiments, the second suitable solvent is chloroform,dichloromethane, nitromethane, dimethylforamide, diethyl ether,tetrahydrofuran, dioxane, dichloroethane, or hexane.

In some embodiments, the second suitable solvent is degassed prior touse.

In some embodiments, step (b) is performed under an inert atmosphere.

In some embodiments, step (b) is carried out at room temperature.

In some embodiments, step (b) is carried out at a temperature of 50-140°C. In some embodiments, step (b) is carried out at a temperature ofabout 80° C.

In some embodiments, step (b) is carried out at a temperature of about120° C.

In some embodiments, the compound is maintained in the second suitablesolvent for 10-50 hours. In some embodiments, the compound is maintainedin the second suitable solvent for about 24 hours.

In some embodiments of step (b), A is a phenyl or pyridine. In someembodiments of step (b), A is a furan, thiophene, pyrrole, thiazole,imidazole, pyrazole, isooxazole, isothiazole, naphthalene, anthracene,pyrimidine, pyrazine, pyridazine, indole, indoline, benzofuran,benzothiophene, or quinolone.

In some embodiments of step (b), the compound produced has thestructure:

wherein

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl); and

R₂, R₃, R₄ and R₅ is each independently —H, halogen, —CN, —CF₃, —OCF₃,-(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH₂,—NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl),—CO₂-(alkyl), —CO₂-(alkenyl), —CO₂-(alkynyl)-CO₂-(aryl),—C(—CO₂-(heteroaryl), —C(O)NH-(alkyl), —C(O)NH-(alkenyl),—C(O)NH-(alkynyl) —C(O)NH-(aryl), —C(O)NH-(heteroaryl), —C(O)N(alkyl)₂,—OH, —OAc, —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl),—O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl),—S-(heteroaryl), pyridine, furan, thiophene, pyrrole, thiazole,imidazole, pyrazole, isooxazole, isothiazole, naphthalene, anthracene,pyrimidine, pyrazine, pyridazine, indole, indoline, benzofuran,benzothiophene, or quinolone.

In some embodiments of the above compound R₂, R₃, R₄ and R₅ is each,independently, —H, halogen, —CN, —CF₃, —OCF₃, -(alkyl), -(alkenyl),-(alkynyl), -(aryl), -(heteroaryl), —NH₂, —NH-(alkyl), —NH-(alkenyl),—NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —CO₂-(alkyl),—CO₂-(alkenyl), —CO₂-(alkynyl)-CO₂-(aryl), —C(—CO₂-(heteroaryl),—C(O)NH-(alkyl), —C(O)NH-(alkenyl), —C(O)NH-(alkynyl) —C(O)NH-(aryl),—C(O)NH-(heteroaryl), —C(O)N(alkyl)₂, —OH, —OAc, —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), pyridine, furan,thiophene, pyrrole, thiazole, imidazole, pyrazole, isooxazole,isothiazole, naphthalene, anthracene, pyrimidine, pyrazine, pyridazine,indole, indoline, benzofuran, benzothiophene, quinolone, pyrazoline,triazole, benzimidazole, benzotriazole, azaindole, or purine.

In some embodiments of the above compound R₂, R₃, R₄ and R₅ is each,independently, —H, pyrazoline, triazole, benzimidazole, benzotriazole,azaindole, or purine.

In some embodiments of step (b), the compound produced has thestructure:

wherein

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl); and

R₂, R₃, R₄ and R₅ is each independently —H, halogen, —CN, —CF₃, —OCF₃,-(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH₂,—NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl),—CO₂-(alkyl), —CO₂-(alkenyl), —CO₂-(alkynyl)-CO₂-(aryl),—C(—CO₂-(heteroaryl), —C(O)NH-(alkyl), —C(O)NH-(alkenyl),—C(O)NH-(alkynyl) —C(O)NH-(aryl), —C(O)NH-(heteroaryl), —C(O)N(alkyl)₂,—OH, —OAc, —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl),—O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl),—S-(heteroaryl), pyridine, furan, thiophene, pyrrole, thiazole,imidazole, pyrazole, isooxazole, isothiazole, naphthalene, anthracene,pyrimidine, pyrazine, pyridazine, indole, indoline, benzofuran,benzothiophene, or quinolone.

In some embodiments of step (b), the compound produced has thestructure:

wherein

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl); and

R₂, R₃ and R₅ is each independently —H, halogen, —CN, —CF₃, —OCF₃,-(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH₂,—NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl),—CO₂-(alkyl), —CO₂-(alkenyl), —CO₂-(alkynyl)-CO₂-(aryl),—C(—CO₂-(heteroaryl), —C(O)NH-(alkyl), —C(O)NH-(alkenyl),—C(O)NH-(alkynyl) —C(O)NH-(aryl), —C(O)NH-(heteroaryl), —C(O)N(alkyl)₂,—OH, —OAc, —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl),—O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl),—S-(heteroaryl), pyridine, furan, thiophene, pyrrole, thiazole,imidazole, pyrazole, isooxazole, isothiazole, naphthalene, anthracene,pyrimidine, pyrazine, pyridazine, indole, indoline, benzofuran,benzothiophene, or quinolone.

In some embodiments of step (b), the compound produced has thestructure:

wherein

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl); and

R₃, R₄ and R₅ is each independently —H, halogen, —CN, —CF₃, —OCF₃,-(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH₂,—NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl),—CO₂-(alkyl), —CO₂-(alkenyl), —CO₂-(alkynyl)-CO₂-(aryl),—C(—CO₂-(heteroaryl), —C(O)NH-(alkyl), —C(O)NH-(alkenyl),—C(O)NH-(alkynyl) —C(O)NH-(aryl), —C(O)NH-(heteroaryl), —C(O)N(alkyl)₂,—OH, —OAc, —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl),—O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl),—S-(heteroaryl), pyridine, furan, thiophene, pyrrole, thiazole,imidazole, pyrazole, isooxazole, isothiazole, naphthalene, anthracene,pyrimidine, pyrazine, pyridazine, indole, indoline, benzofuran,benzothiophene, quinolone, pyrazoline, triazole, benzimidazole,benzotriazole, azaindole, or purine.

The present invention further provides a process of producing atrifluoromethoxylated aryl or trifluoromethoxylated heteroaryl havingthe structure:

wherein

A is an aryl or heteroaryl, each with or without subsutitution; and

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl), comprising:

(a) reacting a compound having the structure:

with a trifluoromethylating agent in the presence of a base in a firstsuitable solvent under conditions to produce a compound having thestructure:

and

(b) maintaining the compound produced in step (a) in a second suitablesolvent under conditions sufficient to produce the trifluoromethoxylatedaryl or trifluormethoxylated heteroaryl having the structure:

In some embodiments of the above process, the first suitable solvent ischloroform, dichloromethane, nitromethane, dimethylforamide, diethylether, tetrahydrofuran, dioxane, dichloroethane, or hexane.

In some embodiments of the above process, the second suitable solvent ischloroform, dichloromethane, nitromethane, dimethylforamide, diethylether, tetrahydrofuran, dioxane, dichloroethane, or hexane.

In some embodiments of the above process, the first suitable solvent andsecond suitable solvent are identical.

In some embodiments of the above process, step (a) and step (b) areperformed by a sequential one-pot synthesis.

In some embodiments of the above process, step (a) and step (b) areperformed by a sequential one-pot synthesis without purification orwork-up in between step (a) and step (b).

In some embodiments of the above process, step (a) and step (b) areperformed by a sequential two-pot synthesis.

In some embodiments of the above process, the compound produced in step(a) is subjected to a work-up prior to step (b).

In some embodiments of the above process, the compound produced in step(a) is subjected to a purification prior to step (b).

In some embodiments of the above process, the compound produced in step(a) is subjected to a work-up and purification prior to step (b).

In some embodiments of the above process, the crude compound produced instep (a) is used in step (b).

In some embodiments of the above process, the first suitable solvent isdegassed prior to use.

In some embodiments of the above process, steps (a) and (b) areperformed under an inert atmosphere.

In some embodiments of the above process, step (a) is carried out atroom temperature.

In some embodiments of the above process, step (b) is carried out atroom temperature.

In some embodiments of the above process, step (b) is carried out at atemperature of 50-140° C.

In some embodiments of the above process, step (b) is carried out at atemperature of about 80° C.

In some embodiments of the above process, step (b) is carried out at atemperature of about 120° C.

In some embodiments of the above process, in step (a) the compound isreacted for 12-24 hours.

In some embodiments of the above process, in step (a) the compound isreacted for about 15 hours.

In some embodiments of the above process, in step (b) the compound ismaintained in the second suitable solvent for 10-50 hours.

In some embodiments of the above process, in step (b) the compound ismaintained in the second suitable solvent for about 24 hours.

In some embodiments of the above process, in step (a) the molar ratio ofthe compound to the trifluormethylation agent is 1:1 to 1:2.

In some embodiments of the above process, in step (a) the molar ratio ofthe compound to the trifluormethylation agent is 1:1.2.

In some embodiments of the above process, the trifluormethylating agentis Togni reagent or Togni reagent II.

In some embodiments of the above process, the base is sodium hydride orcesium carbonate.

In some embodiments of the above process, A is a phenyl or pyridine.

In some embodiments of the above process, A is a furan, thiophene,pyrrole, thiazole, imidazole, pyrazole, isooxazole, isothiazole,naphthalene, anthracene, pyrimidine, pyrazine, pyridazine, indole,indoline, benzofuran, benzothiophene, or quinolone.

In some embodiments of the above process, the compound produced has thestructure:

wherein

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl); and

R₂, R₃, R₄ and R₅ is each independently —H, halogen, —CN, —CF₃, —OCF₃,-(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH₂,—NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl),—CO₂-(alkyl), —CO₂-(alkenyl), —CO₂-(alkynyl)-CO₂-(aryl),—C(—CO₂-(heteroaryl), —C(O)NH-(alkyl), —C(O)NH-(alkenyl),—C(O)NH-(alkynyl) —C(O)NH-(aryl), —C(O)NH-(heteroaryl), —C(O)N(alkyl)₂,—OH, —OAc, —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl),—O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl),—S-(heteroaryl), pyridine, furan, thiophene, pyrrole, thiazole,imidazole, pyrazole, isooxazole, isothiazole, naphthalene, anthracene,pyrimidine, pyrazine, pyridazine, indole, indoline, benzofuran,benzothiophene, or quinolone.

In some embodiments of the above compound R₂, R₃, R₄ and R₅ is each,independently, —H, halogen, —CN, —CF₃, —OCF₃, -(alkyl), -(alkenyl),-(alkynyl), -(aryl), -(heteroaryl), —NH₂, —NH-(alkyl), —NH-(alkenyl),—NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —CO₂-(alkyl),—CO₂-(alkenyl), —CO₂-(alkynyl)-CO₂-(aryl), —C(—CO₂-(heteroaryl),—C(O)NH-(alkyl), —C(O)NH-(alkenyl), —C(O)NH-(alkynyl) —C(O)NH-(aryl),—C(O)NH-(heteroaryl), —C(O)N(alkyl)₂, —OH, —OAc, —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), pyridine, furan,thiophene, pyrrole, thiazole, imidazole, pyrazole, isooxazole,isothiazole, naphthalene, anthracene, pyrimidine, pyrazine, pyridazine,indole, indoline, benzofuran, benzothiophene, quinolone, pyrazoline,triazole, benzimidazole, benzotriazole, azaindole, or purine.

In some embodiments of the above compound R₂, R₃, R₄ and R₅ is each,independently, —H, pyrazoline, triazole, benzimidazole, benzotriazole,azaindole, or purine.

In some embodiments of the above process, the compound produced has thestructure:

wherein

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl); and

R₂, R₃, R₄ and R₅ is each independently —H, halogen, —CN, —CF₃, —OCF₃,-(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH₂,—NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl),—CO₂-(alkyl), —CO₂-(alkenyl), —CO₂-(alkynyl)-CO₂-(aryl),—C(—CO₂-(heteroaryl), —C(O)NH-(alkyl), —C(O)NH-(alkenyl),—C(O)NH-(alkynyl) —C(O)NH-(aryl), —C(O)NH-(heteroaryl), —C(O)N(alkyl)₂,—OH, —OAc, —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl),—O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl),—S-(heteroaryl), pyridine, furan, thiophene, pyrrole, thiazole,imidazole, pyrazole, isooxazole, isothiazole, naphthalene, anthracene,pyrimidine, pyrazine, pyridazine, indole, indoline, benzofuran,benzothiophene, or quinolone.

In some embodiments of the above process, the compound produced has thestructure:

wherein

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl); and

R₂, R₃ and R₅ is each independently —H, halogen, —CN, —CF₃, —OCF₃,-(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH₂,—NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl),—CO₂-(alkyl), —CO₂-(alkenyl), —CO₂-(alkynyl)-CO₂-(aryl),—C(—CO₂-(heteroaryl), —C(O)NH-(alkyl), —C(O)NH-(alkenyl),—C(O)NH-(alkynyl) —C(O)NH-(aryl), —C(O)NH-(heteroaryl), —C(O)N(alkyl)₂,—OH, —OAc, —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl),—O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl),—S-(heteroaryl), pyridine, furan, thiophene, pyrrole, thiazole,imidazole, pyrazole, isooxazole, isothiazole, naphthalene, anthracene,pyrimidine, pyrazine, pyridazine, indole, indoline, benzofuran,benzothiophene, or quinolone.

In some embodiments of the above process, the compound produced has thestructure:

wherein

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl); and

R₃, R₄ and R₅ is each independently —H, halogen, —CN, —CF₃, —OCF₃,-(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH₂,—NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl),—CO₂-(alkyl), —CO₂-(alkenyl), —CO₂-(alkynyl)-CO₂-(aryl),—C(—CO₂-(heteroaryl), —C(O)NH-(alkyl), —C(O)NH-(alkenyl),—C(O)NH-(alkynyl) —C(O)NH-(aryl), —C(O)NH-(heteroaryl), —C(O)N(alkyl)₂,—OH, —OAc, —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl),—O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl),—S-(heteroaryl), pyridine, furan, thiophene, pyrrole, thiazole,imidazole, pyrazole, isooxazole, isothiazole, naphthalene, anthracene,pyrimidine, pyrazine, pyridazine, indole, indoline, benzofuran,benzothiophene, quinolone, pyrazoline, triazole, benzimidazole,benzotriazole, azaindole, or purine.

In some embodiments, the process comprising:

(a) reacting a compound having the structure:

with Togni reagent II in the presence of a base in a first suitablesolvent under conditions sufficient to produce a compound having thestructure:

and

(b) maintaining the compound produced in step (a) in a second suitablesolvent under conditions sufficient to produce the trifluoromethoxylatedaryl or trifluormethoxylated heteroaryl having the structure:

In some embodiments, the process comprising:

(a) reacting a compound having the structure:

with Togni reagent II in the presence of cesium carbonate in chloroformor dichloromethane under conditions sufficient to produce a compoundhaving the structure:

and

(b) maintaining the compound produced in step (a) in nitromethane underconditions sufficient to produce the trifluoromethoxylated aryl ortrifluormethoxylated heteroaryl having the structure:

In some embodiments, the compound produced has the structure:

wherein

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)2,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl); and

R₆, R₇, R₈, R₉, and R₁₀ is each independently —H, halogen, —CN, —CF₃,—OCF₃, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH₂,—NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl),—CO₂-(alkyl), —CO₂-(alkenyl), —CO₂-(alkynyl)-CO₂-(aryl),—C(—CO₂-(heteroaryl), —C(O)NH-(alkyl), —C(O)NH-(alkenyl),—C(O)NH-(alkynyl) —C(O)NH-(aryl), —C(O)NH-(heteroaryl), —C(O)N(alkyl)₂,—OH, —OAc, —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl),—O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl),—S-(heteroaryl), pyridine, furan, thiophene, pyrrole, thiazole,imidazole, pyrazole, isooxazole, isothiazole, naphthalene, anthracene,pyrimidine, pyrazine, pyridazine, indole, indoline, benzofuran,benzothiophene, or quinolone.

In some embodiments, the compound produced has the structure:

wherein

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl); and

R₁₁, R₁₂, R₁₃, R₁₄, and R₁₅ is each independently —H, halogen, —CN,—CF₃, —OCF₃, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),—NH₂, —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl),—NH-(heteroaryl), —CO₂-(alkyl), —CO₂-(alkenyl),—CO₂-(alkynyl)-CO₂-(aryl), —C(—CO₂-(heteroaryl), —C(O)NH-(alkyl),—C(O)NH-(alkenyl), —C(O)NH-(alkynyl) —C(O)NH-(aryl),—C(O)NH-(heteroaryl), —C(O)N(alkyl)₂, —OH, —OAc, —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), pyridine, furan,thiophene, pyrrole, thiazole, imidazole, pyrazole, isooxazole,isothiazole, naphthalene, anthracene, pyrimidine, pyrazine, pyridazine,indole, indoline, benzofuran, benzothiophene, or quinolone.

In some embodiments, the phenyl, pyridine, furan, thiophene, pyrrole,thiazole, imidazole, pyrazole, isooxazole, isothiazole, naphthalene,anthracene, pyrimidine, pyrazine, pyridazine, indole, indoline,benzofuran, benzothiophene, quinolone or quinazolinone is substitutedwith one or more of the following: halogen, —CN, —CF₃, —OCF₃, -(alkyl),-(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH₂, —NH-(alkyl),—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —CO₂-(alkyl),—CO₂-(alkenyl), —CO₂-(alkynyl)-CO₂-(aryl), —C(—CO₂-(heteroaryl),—C(O)NH-(alkyl), —C(O)NH-(alkenyl), —C(O)NH-(alkynyl) —C(O)NH-(aryl),—C(O)NH-(heteroaryl), —C(O)N(alkyl)₂, —OH, —OAc, —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), or an amino acidor protected amino acid.

In some embodiments, a process of producing a compound having thestructure:

wherein

A is an aryl or heteroaryl, each with or without subsutitution; and

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)2,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl), comprising:

(a) reacting a compound having the structure:

with a trifluoromethylating agent in the presence of a base in a firstsuitable solvent to produce the compound having the structure:

In some embodiments, a process of producing a trifluoromethoxylated arylor trifluoromethoxylated heteroaryl having the structure:

wherein

A is an aryl or heteroaryl, each with or without subsutitution; and

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)2,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl), comprising:

(b) maintaining the compound having the structure:

in a second suitable solvent to produce the trifluoromethoxylated arylor trifluormethoxylated heteroaryl having the structure:

The present invention further provides a process of producing atrifluoromethoxylated aryl or trifluoromethoxylated heteroaryl havingthe structure:

wherein

A is an aryl or heteroaryl, each with or without subsutitution; and

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)2,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl), comprising:

(a) reacting a compound having the structure:

with a trifluoromethylating agent in the presence of a base in a firstsuitable solvent to produce a compound having the structure:

and

(b) maintaining the compound produced in step (a) in a second suitablesolvent to produce the trifluoromethoxylated aryl ortrifluormethoxylated heteroaryl having the structure:

The present invention also provides a process of producing atrifluoromethoxylated aryl or trifluoromethoxylated heteroaryl havingthe structure:

wherein

A is an aryl or heteroaryl, each with or without subsutitution; and

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl),

comprising:

(a) reacting a compound having the structure:

with a trifluoromethylating agent in a first suitable solvent underconditions to produce a compound having the structure:

and

(b) maintaining the compound produced in step (a) in the first suitablesolvent under conditions sufficient to produce the trifluoromethoxylatedaryl or trifluormethoxylated heteroaryl having the structure:

In some embodiments of the above process, A is a phenyl or pyridine.

In some embodiments of the above process, A is pyridine.

In some embodiments of the above process, the first suitable solvent ischloroform, dichloromethane, nitromethane, dimethylforamide, diethylether, tetrahydrofuran, dioxane, dichloroethane, or hexane.

In some embodiments of the above process, wherein trifluormethylatingagent is Togni reagent I or Togni reagent II. The present invention alsoprovides a compound having the structure:

wherein

A is an aryl or heteroaryl, each with or without subsutitution; and

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl).

In some embodiments of the compound, A is a phenyl or pyridine. In someembodiments of the compound, A is a furan, thiophene, pyrrole, thiazole,imidazole, pyrazole, isooxazole, isothiazole, naphthalene, anthracene,pyrimidine, pyrazine, pyridazine, indole, indoline, benzofuran,benzothiophene, or quinolone,

or a salt or ester thereof.

In some embodiments, a compound having the structure:

wherein

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl); and

R₂, R₃, R₄ and R₅ is each independently —H, halogen, —CN, —CF₃, —OCF₃,-(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH₂,—NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl),—CO₂-(alkyl), —CO₂-(alkenyl), —CO₂-(alkynyl)-CO₂-(aryl),—C(—CO₂-(heteroaryl), —C(O)NH-(alkyl), —C(O)NH-(alkenyl),—C(O)NH-(alkynyl) —C(O)NH-(aryl), —C(O)NH-(heteroaryl), —C(O)N(alkyl)₂,—OH, —OAc, —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl),—O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl),—S-(heteroaryl), pyridine, furan, thiophene, pyrrole, thiazole,imidazole, pyrazole, isooxazole, isothiazole, naphthalene, anthracene,pyrimidine, pyrazine, pyridazine, indole, indoline, benzofuran,benzothiophene, or quinolone.

In some embodiments of the above compound R₂, R₃, R₄ and R₅ is each,independently, —H, halogen, —CN, —CF₃, —OCF₃, -(alkyl), -(alkenyl),-(alkynyl), -(aryl), -(heteroaryl), —NH₂, —NH-(alkyl), —NH-(alkenyl),—NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —CO₂-(alkyl),—CO₂-(alkenyl), —CO₂-(alkynyl)-CO₂-(aryl), —C(—CO₂-(heteroaryl),—C(O)NH-(alkyl), —C(O)NH-(alkenyl), —C(O)NH-(alkynyl) —C(O)NH-(aryl),—C(O)NH-(heteroaryl), —C(O)N(alkyl)₂, —OH, —OAc, —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), pyridine, furan,thiophene, pyrrole, thiazole, imidazole, pyrazole, isooxazole,isothiazole, naphthalene, anthracene, pyrimidine, pyrazine, pyridazine,indole, indoline, benzofuran, benzothiophene, quinolone, pyrazoline,triazole, benzimidazole, benzotriazole, azaindole, or purine.

In some embodiments of the above compound R₂, R₃, R₄ and R₅ is each,independently, —H, pyrazoline, triazole, benzimidazole, benzotriazole,azaindole, or purine.

In some embodiments, a compound having the structure:

wherein

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), or —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl); and

R₂, R₃, R₄ and R₅ is each independently —H, halogen, —CN, —CF₃, —OCF₃,-(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH₂,—NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl),—CO₂-(alkyl), —CO₂-(alkenyl), —CO₂-(alkynyl)-CO₂-(aryl),—C(—CO₂-(heteroaryl), —C(O)NH-(alkyl), —C(O)NH-(alkenyl),—C(O)NH-(alkynyl) —C(O)NH-(aryl), —C(O)NH-(heteroaryl), —C(O)N(alkyl)₂,—OH, —OAc, —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl),—O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl),—S-(heteroaryl), pyridine, furan, thiophene, pyrrole, thiazole,imidazole, pyrazole, isooxazole, isothiazole, naphthalene, anthracene,pyrimidine, pyrazine, pyridazine, indole, indoline, benzofuran,benzothiophene, or quinolone.

In some embodiments, a compound having the structure:

wherein

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), or —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl); and

R₂, R₃, and R₅ is each independently —H, halogen, —CN, —CF₃, —OCF₃,-(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH₂,—NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl),—CO₂-(alkyl), —CO₂-(alkenyl), —CO₂-(alkynyl)-CO₂-(aryl),—C(—CO₂-(heteroaryl), —C(O)NH-(alkyl), —C(O)NH-(alkenyl),—C(O)NH-(alkynyl) —C(O)NH-(aryl), —C(O)NH-(heteroaryl), —C(O)N(alkyl)₂,—OH, —OAc, —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl),—O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl),—S-(heteroaryl), pyridine, furan, thiophene, pyrrole, thiazole,imidazole, pyrazole, isooxazole, isothiazole, naphthalene, anthracene,pyrimidine, pyrazine, pyridazine, indole, indoline, benzofuran,benzothiophene, or quinolone.

The present invention also provides a compound having the structure:

wherein

A is an aryl or heteroaryl, each with or without subsutitution; and

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl),

or a salt or ester thereof.

In some embodiments of the compound, A is a phenyl or pyridine. In someembodiments of the compound, A is a furan, thiophene, pyrrole, thiazole,imidazole, pyrazole, isooxazole, isothiazole, naphthalene, anthracene,pyrimidine, pyrazine, pyridazine, indole, indoline, benzofuran,benzothiophene, or quinolone.

In some embodiments, a compound having the structure:

wherein

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl); and

R₂, R₃, R₄ and R₅ is each independently —H, halogen, —CN, —CF₃, —OCF₃,-(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH₂,—NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl),—CO₂-(alkyl), —CO₂-(alkenyl), —CO₂-(alkynyl)-CO₂-(aryl),—C(—CO₂-(heteroaryl), —C(O)NH-(alkyl), —C(O)NH-(alkenyl),—C(O)NH-(alkynyl) —C(O)NH-(aryl), —C(O)NH-(heteroaryl), —C(O)N(alkyl)₂,—OH, —OAc, —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl),—O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl),—S-(heteroaryl), pyridine, furan, thiophene, pyrrole, thiazole,imidazole, pyrazole, isooxazole, isothiazole, naphthalene, anthracene,pyrimidine, pyrazine, pyridazine, indole, indoline, benzofuran,benzothiophene, or quinolone.

In some embodiments, a compound having the structure:

wherein

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), or —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl); and

R₂, R₃, R₄ and R₅ is each independently —H, halogen, —CN, —CF₃, —OCF₃,-(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH₂,—NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl),—CO₂-(alkyl), —CO₂-(alkenyl), —CO₂-(alkynyl)-CO₂-(aryl),—C(—CO₂-(heteroaryl), —C(O)NH-(alkyl), —C(O)NH-(alkenyl),—C(O)NH-(alkynyl) —C(O)NH-(aryl), —C(O)NH-(heteroaryl), —C(O)N(alkyl)₂,—OH, —OAc, —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl),—O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl),—S-(heteroaryl), pyridine, furan, thiophene, pyrrole, thiazole,imidazole, pyrazole, isooxazole, isothiazole, naphthalene, anthracene,pyrimidine, pyrazine, pyridazine, indole, indoline, benzofuran,benzothiophene, or quinolone.

In some embodiments, a compound having the structure:

wherein

R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),-(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), or —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl); and

R₂, R₃, and R₅ is each independently —H, halogen, —CN, —CF₃, —OCF₃,-(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH₂,—NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl),—CO₂-(alkyl), —CO₂-(alkenyl), —CO₂-(alkynyl)-CO₂-(aryl),—C(—CO₂-(heteroaryl), —C(O)NH-(alkyl), —C(O)NH-(alkenyl),—C(O)NH-(alkynyl) —C(O)NH-(aryl), —C(O)NH-(heteroaryl), —C(O)N(alkyl)₂,—OH, —OAc, —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl),—O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl),—S-(heteroaryl), pyridine, furan, thiophene, pyrrole, thiazole,imidazole, pyrazole, isooxazole, isothiazole, naphthalene, anthracene,pyrimidine, pyrazine, pyridazine, indole, indoline, benzofuran,benzothiophene, or quinolone.

In some embodiments of any of the disclosed processes or compounds, R₂,R₃, R₄ and R₅ is each, independently, —H, halogen, —CN, —CF₃, —OCF₃,-(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH₂,—NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl),—C₂-(alkyl), —CO₂-(alkenyl), —CO₂-(alkynyl)-CO₂-(aryl),—C(—CO₂-(heteroaryl), —C(O)NH-(alkyl), —C(O)NH-(alkenyl),—C(O)NH-(alkynyl) —C(O)NH-(aryl), —C(O)NH-(heteroaryl), —C(O)N(alkyl)₂,—OH, —OAc, —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl),—O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl),—S-(heteroaryl), pyridine, furan, thiophene, pyrrole, thiazole,imidazole, pyrazole, isooxazole, isothiazole, naphthalene, anthracene,pyrimidine, pyrazine, pyridazine, indole, indoline, benzofuran,benzothiophene, quinolone, pyrazoline, triazole, benzimidazole,benzotriazole, azaindole, or purine, or any combination thereof.

In some embodiments of any of the disclosed processes or compounds, R₂,R₃, R₄ and R₅ is each, independently, —H, pyrazoline, triazole,benzimidazole, benzotriazole, azaindole, or purine, or any combinationthereof.

In some embodiments of any of the disclosed processes or compounds, R₆,R₇, Re, R₉ and R₁₀ is each, independently, —H, halogen, —CN, —CF₃,—OCF₃, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH₂,—NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl),—CO₂-(alkyl), —CO₂-(alkenyl), —CO₂-(alkynyl)-CO₂-(aryl),—C(—CO₂-(heteroaryl), —C(O)NH-(alkyl), —C(O)NH-(alkenyl),—C(O)NH-(alkynyl) —C(O)NH-(aryl), —C(O)NH-(heteroaryl), —C(O)N(alkyl)₂,—OH, —OAc, —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl),—O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl),—S-(heteroaryl), pyridine, furan, thiophene, pyrrole, thiazole,imidazole, pyrazole, isooxazole, isothiazole, naphthalene, anthracene,pyrimidine, pyrazine, pyridazine, indole, indoline, benzofuran,benzothiophene, quinolone, pyrazoline, triazole, benzimidazole,benzotriazole, azaindole, or purine, or any combination thereof.

In some embodiments of any of the disclosed processes or compounds, R₆,R₇, R₈, R₉ and R₁₀ is each, independently, —H, pyrazoline, triazole,benzimidazole, benzotriazole, azaindole, or purine, or any combinationthereof.

In some embodiments of any of the disclosed processes or compounds, R₁₁,R₁₂, R₁₃, R₁₄ and R₁₅ is each, independently, —H, halogen, —CN, —CF₃,—OCF₃, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH₂,—NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl),—CO₂-(alkyl), —CO₂-(alkenyl), —CO₂-(alkynyl)-CO₂-(aryl),—C(—CO₂-(heteroaryl), —C(O)NH-(alkyl), —C(O)NH-(alkenyl),—C(O)NH-(alkynyl) —C(O)NH-(aryl), —C(O)NH-(heteroaryl), —C(O)N(alkyl)₂,—OH, —OAc, —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl),—O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl),—S-(heteroaryl), pyridine, furan, thiophene, pyrrole, thiazole,imidazole, pyrazole, isooxazole, isothiazole, naphthalene, anthracene,pyrimidine, pyrazine, pyridazine, indole, indoline, benzofuran,benzothiophene, quinolone, pyrazoline, triazole, benzimidazole,benzotriazole, azaindole, or purine, or any combination thereof.

In some embodiments of any of the disclosed processes or compounds, R₁₁,R₁₂, R₁₃, R₁₄ and R₁₅ is each, independently, —H, pyrazoline, triazole,benzimidazole, benzotriazole, azaindole, or purine, or any combinationthereof.

In some embodiments, the compound of step (a) is purified by columnchromatography prior to step (b).

In some embodiments, the trifluoromethylating reagent is1-Trifluoromethyl-1,2-benziodoxol-3-(1H)-one (Togni reagent II), whichmay be purchased from Sigma Aldrich, St. Louis, Mo., USA (Catalog#771147). In some embodiments, the trifluoromethylating reagent is3,3-Dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (Togni reagent I),which may be purchased from Sigma Aldrich, St. Louis, Mo., USA (Catalog#696641).

In some embodiments, the first or second suitable solvent include, butare not limited to, inert organic solvents or mixtures thereof.

The process described herein is advantageous in that it avoids the needfor highly toxic and thermally labile reagents, which is notparticularly desirable for industrial implementation due to the hazardsassociated with such reagents.

The process described herein is also advantageous in that it may beperformed in one-pot. The process described herein is furtheradvantageous in that it avoids the need for highly toxic metalcontaining reagents.

The present reaction occurs under reaction conditions sufficient toproduce the desired compound. Such conditions, e.g. temperature, time,molarity, etc., may be varied by one of ordinary skill in the art basedon the methods and protocols described herein.

Where a range is given in the specification it is understood that therange includes all integers and 0.1 units within that range, and anysub-range thereof. For example, a range of 77 to 90% is a disclosure of77, 78, 79, 80, and 81% etc.

As used herein, “about” with regard to a stated number encompasses arange of +one percent to −one percent of the stated value. By way ofexample, about 100 mg/kg therefore includes 99, 99.1, 99.2, 99.3, 99.4,99.5, 99.6, 99.7, 99.8, 99.9, 100, 100.1, 100.2, 100.3, 100.4, 100.5,100.6, 100.7, 100.8, 100.9 and 101 mg/kg. Accordingly, about 100 mg/kgincludes, in an embodiment, 100 mg/kg.

It is understood that where a parameter range is provided, all integerswithin that range, and tenths thereof, are also provided by theinvention. For example, “0.2-5 mg/kg/day” is a disclosure of 0.2mg/kg/day, 0.3 mg/kg/day, 0.4 mg/kg/day, 0.5 mg/kg/day, 0.6 mg/kg/dayetc. up to 5.0 mg/kg/day.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. Thus, C₁-C_(n) as in “C₁-C_(n) alkyl”is defined to include groups having 1, 2 . . . , n−1 or n carbons in alinear or branched arrangement, and specifically includes methyl, ethyl,propyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, sec-butyl andso on. An embodiment can be C₁-C₁₂ alkyl, C₂-C₁₂ alkyl, C₃-C₁₂ alkyl,C₄-C₁₂ alkyl and so on. An embodiment can be C₁-C₈ alkyl, C₂-C₈ alkyl,C₃-C₈ alkyl, C₄-C₈ alkyl and so on. “Alkoxy” represents an alkyl groupas described above attached through an oxygen bridge.

The term “alkenyl” refers to a non-aromatic hydrocarbon radical,straight or branched, containing at least 1 carbon to carbon doublebond, and up to the maximum possible number of non-aromaticcarbon-carbon double bonds may be present. Thus, C₂-C_(n) alkenyl isdefined to include groups having 1, 2 . . . , n−1 or n carbons. Forexample, “C₂-C₆ alkenyl” means an alkenyl radical having 2, 3, 4, 5, or6 carbon atoms, and at least 1 carbon-carbon double bond, and up to, forexample, 3 carbon-carbon double bonds in the case of a C₆ alkenyl,respectively. Alkenyl groups include ethenyl, propenyl, butenyl andcyclohexenyl. As described above with respect to alkyl, the straight,branched or cyclic portion of the alkenyl group may contain double bondsand may be substituted if a substituted alkenyl group is indicated. Anembodiment can be C₂-C₁₂ alkenyl or C₂-C₈ alkenyl.

The term “alkynyl” refers to a hydrocarbon radical straight or branched,containing at least 1 carbon to carbon triple bond, and up to themaximum possible number of non-aromatic carbon-carbon triple bonds maybe present. Thus, C₂-C_(n) alkynyl is defined to include groups having1, 2 . . . , n−1 or n carbons. For example, “C₂-C₆ alkynyl” means analkynyl radical having 2 or 3 carbon atoms, and 1 carbon-carbon triplebond, or having 4 or 5 carbon atoms, and up to 2 carbon-carbon triplebonds, or having 6 carbon atoms, and up to 3 carbon-carbon triple bonds.Alkynyl groups include ethynyl, propynyl and butynyl. As described abovewith respect to alkyl, the straight or branched portion of the alkynylgroup may contain triple bonds and may be substituted if a substitutedalkynyl group is indicated. An embodiment can be a C₂-C_(n) alkynyl. Anembodiment can be C₂-C₁₂ alkynyl or C₃-C₈ alkynyl.

As used herein, “aryl” is intended to mean any stable monocyclic,bicyclic or polycyclic carbon ring of up to 10 atoms in each ring,wherein at least one ring is aromatic, and may be unsubstituted orsubstituted. Examples of such aryl elements include but are not limitedto: phenyl, p-toluenyl (4-methylphenyl), naphthyl, tetrahydro-naphthyl,indanyl, phenanthryl, anthryl or acenaphthyl. In cases where the arylsubstituent is bicyclic and one ring is non-aromatic, it is understoodthat attachment is via the aromatic ring. The term “heteroaryl”, as usedherein, represents a stable monocyclic, bicyclic or polycyclic ring ofup to 10 atoms in each ring, wherein at least one ring is aromatic andcontains from 1 to 4 heteroatoms selected from the group consisting ofO, N and S. Bicyclic aromatic heteroaryl groups include phenyl,pyridine, pyrimidine or pyridazine rings that are (a) fused to a6-membered aromatic (unsaturated) heterocyclic ring having one nitrogenatom; (b) fused to a 5- or 6-membered aromatic (unsaturated)heterocyclic ring having two nitrogen atoms; (c) fused to a 5-memberedaromatic (unsaturated) heterocyclic ring having one nitrogen atomtogether with either one oxygen or one sulfur atom; or (d) fused to a5-membered aromatic (unsaturated) heterocyclic ring having oneheteroatom selected from O, N or S. Heteroaryl groups within the scopeof this definition include but are not limited to: benzoimidazolyl,benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl,benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl,furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl,isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl,oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl,pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl,triazolyl, azetidinyl, aziridinyl, 1,4-dioxanyl, hexahydroazepinyl,dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl,dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl,dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl,dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, tetrahydrothienyl, acridinyl,carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl,benzotriazolyl, benzothiazolyl, benzoxazolyl, isoxazolyl, isothiazolyl,furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl,oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl,pyrimidinyl, pyrrolyl, tetra-hydroquinoline. In cases where theheteroaryl substituent is bicyclic and one ring is non-aromatic orcontains no heteroatoms, it is understood that attachment is via thearomatic ring or via the heteroatom containing ring, respectively. Ifthe heteroaryl contains nitrogen atoms, it is understood that thecorresponding N-oxides thereof are also encompassed by this definition.

The term “substitution”, “substituted” and “substituent” refers to afunctional group as described above in which one or more bonds to ahydrogen atom contained therein are replaced by a bond to non-hydrogenor non-carbon atoms, provided that normal valencies are maintained andthat the substitution results in a stable compound. Substituted groupsalso include groups in which one or more bonds to a carbon(s) orhydrogen(s) atom are replaced by one or more bonds, including double ortriple bonds, to a heteroatom. Examples of substituent groups includethe functional groups described above, and halogens (i.e., F, Cl, Br,and I); alkyl groups, such as methyl, ethyl, n-propyl, isopropryl,n-butyl, tert-butyl, and trifluoromethyl; hydroxyl; alkoxy groups, suchas methoxy, ethoxy, n-propoxy, and isopropoxy; aryloxy groups, such asphenoxy; arylalkyloxy, such as benzyloxy (phenylmethoxy) andp-trifluoromethylbenzyloxy (4-trifluoromethylphenylmethoxy);heteroaryloxy groups; sulfonyl groups, such as trifluoromethanesulfonyl,methanesulfonyl, and p-toluenesulfonyl; nitro, nitrosyl; mercapto;sulfanyl groups, such as methylsulfanyl, ethylsulfanyl andpropylsulfanyl; cyano; amino groups, such as amino, methylamino,dimethylamino, ethylamino, and diethylamino, protected amino; ester oralkyl ester; and carboxyl. Where multiple substituent moieties aredisclosed or claimed, the substituted compound can be independentlysubstituted by one or more of the disclosed or claimed substituentmoieties, singly or plurality. By independently substituted, it is meantthat the (two or more) substituents can be the same or different.

The starting materials used in the method of the present invention maybe prepared by techniques well known in organic synthesis and familiarto a practitioner ordinarily skilled in the art. However, these may notbe the only means by which to synthesize or obtain the desiredcompounds.

The starting materials used in the method of the present invention maybe prepared by techniques described in Vogel's Textbook of PracticalOrganic Chemistry, A. I. Vogel, A. R. Tatchell, B. S. Furnis, A. J.Hannaford, P. W. G. Smith, (Prentice Hall) 5^(th) Edition (1996),March's Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, Michael B. Smith, Jerry March, (Wiley-Interscience) 5^(th)Edition (2007), and references therein, which are incorporated byreference herein. However, these may not be the only means by which tosynthesize or obtain the desired compounds.

The reaction conditions used in the present invention may be varied bytechniques well known in organic synthesis and familiar to apractitioner ordinarily skilled in the art to provide conditionssufficient to produce the desired product. Such techniques are describedin Vogel's Textbook of Practical Organic Chemistry, A. I. Vogel, A. R.Tatchell, B. S. Furnis, A. J. Hannaford, P. W. G. Smith, (Prentice Hall)5^(th) Edition (1996), March's Advanced Organic Chemistry: Reactions,Mechanisms, and Structure, Michael B. Smith, Jerry March,(Wiley-Interscience) 5^(th) Edition (2007), and references therein,which are incorporated by reference herein.

In the compounds in the process of the present invention, alkyl,alkenyl, alkynyl, aryl, heteroaryl groups can be further substituted byreplacing one or more hydrogen atoms with alternative non-hydrogengroups.

Another aspect of the invention comprises a compound used in the methodof the present invention as a pharmaceutical composition.

In some embodiments, a pharmaceutical composition comprising thecompound of the present invention and a pharmaceutically acceptablecarrier.

As used herein, the term “pharmaceutically active agent” means anysubstance or compound suitable for administration to a subject andfurnishes biological activity or other direct effect in the treatment,cure, mitigation, diagnosis, or prevention of disease, or affects thestructure or any function of the subject. Pharmaceutically active agentsinclude, but are not limited to, substances and compounds described inthe Physicians' Desk Reference (PDR Network, LLC; 64th edition; Nov. 15,2009) and “Approved Drug Products with Therapeutic EquivalenceEvaluations” (U.S. Department Of Health And Human Services, 30^(th)edition, 2010), which are hereby incorporated by reference.Pharmaceutically active agents which have pendant carboxylic acid groupsmay be modified in accordance with the present invention using standardesterification reactions and methods readily available and known tothose having ordinary skill in the art of chemical synthesis. Where apharmaceutically active agent does not possess a carboxylic acid group,the ordinarily skilled artisan will be able to design and incorporate acarboxylic acid group into the pharmaceutically active agent whereesterification may subsequently be carried out so long as themodification does not interfere with the pharmaceutically active agent'sbiological activity or effect. The compounds used in the method of thepresent invention may be in a salt form. As used herein, a “salt” is asalt of the instant compounds which has been modified by making acid orbase salts of the compounds. In the case of compounds used to treat aninfection or disease caused by a pathogen, the salt is pharmaceuticallyacceptable. Examples of pharmaceutically acceptable salts include, butare not limited to, mineral or organic acid salts of basic residues suchas amines; alkali or organic salts of acidic residues such as phenols.The salts can be made using an organic or inorganic acid. Such acidsalts are chlorides, bromides, sulfates, nitrates, phosphates,sulfonates, formates, tartrates, maleates, malates, citrates, benzoates,salicylates, ascorbates, and the like. Phenolate salts are the alkalineearth metal salts, sodium, potassium or lithium. The term“pharmaceutically acceptable salt” in this respect, refers to therelatively non-toxic, inorganic and organic acid or base addition saltsof compounds of the present invention. These salts can be prepared insitu during the final isolation and purification of the compounds of theinvention, or by separately reacting a purified compound of theinvention in its free base or free acid form with a suitable organic orinorganic acid or base, and isolating the salt thus formed.Representative salts include the hydrobromide, hydrochloride, sulfate,bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate,stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate,maleate, fumarate, succinate, tartrate, napthylate, mesylate,glucoheptonate, lactobionate, and laurylsulphonate salts and the like.(See, e.g., Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci.66:1-19).

The compounds of the present invention may also form salts with basicamino acids such a lysine, arginine, etc. and with basic sugars such asN-methylglucamine, 2-amino-2-deoxyglucose, etc. and any otherphysiologically non-toxic basic substance.

As used herein, “administering” an agent may be performed using any ofthe various methods or delivery systems well known to those skilled inthe art. The administering can be performed, for example, orally,parenterally, intraperitoneally, intravenously, intraarterially,transdermally, sublingually, intramuscularly, rectally, transbuccally,intranasally, liposomally, via inhalation, vaginally, intraoccularly,via local delivery, subcutaneously, intraadiposally, intraarticularly,intrathecally, into a cerebral ventricle, intraventicularly,intratumorally, into cerebral parenchyma or intraparenchchymally.

The compounds used in the method of the present invention may beadministered in various forms, including those detailed herein. Thetreatment with the compound may be a component of a combination therapyor an adjunct therapy, i.e. the subject or patient in need of the drugis treated or given another drug for the disease in conjunction with oneor more of the instant compounds. This combination therapy can besequential therapy where the patient is treated first with one drug andthen the other or the two drugs are given simultaneously. These can beadministered independently by the same route or by two or more differentroutes of administration depending on the dosage forms employed.

As used herein, a “pharmaceutically acceptable carrier” is apharmaceutically acceptable solvent, suspending agent or vehicle, fordelivering the instant compounds to the animal or human. The carrier maybe liquid or solid and is selected with the planned manner ofadministration in mind. Liposomes are also a pharmaceutically acceptablecarrier as are slow-release vehicles.

The dosage of the compounds administered in treatment will varydepending upon factors such as the pharmacodynamic characteristics of aspecific chemotherapeutic agent and its mode and route ofadministration; the age, sex, metabolic rate, absorptive efficiency,health and weight of the recipient; the nature and extent of thesymptoms; the kind of concurrent treatment being administered; thefrequency of treatment with; and the desired therapeutic effect.

A dosage unit of the compounds used in the method of the presentinvention may comprise a single compound or mixtures thereof withadditional antitumor agents. The compounds can be administered in oraldosage forms as tablets, capsules, pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. The compounds may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, or introduced directly, e.g. byinjection, topical application, or other methods, into or topically ontoa site of disease or lesion, all using dosage forms well known to thoseof ordinary skill in the pharmaceutical arts.

The compounds used in the method of the present invention can beadministered in admixture with suitable pharmaceutical diluents,extenders, excipients, or in carriers such as the novel programmablesustained-release multi-compartmental nanospheres (collectively referredto herein as a pharmaceutically acceptable carrier) suitably selectedwith respect to the intended form of administration and as consistentwith conventional pharmaceutical practices. The unit will be in a formsuitable for oral, nasal, rectal, topical, intravenous or directinjection or parenteral administration. The compounds can beadministered alone or mixed with a pharmaceutically acceptable carrier.This carrier can be a solid or liquid, and the type of carrier isgenerally chosen based on the type of administration being used. Theactive agent can be co-administered in the form of a tablet or capsule,liposome, as an agglomerated powder or in a liquid form. Examples ofsuitable solid carriers include lactose, sucrose, gelatin and agar.Capsule or tablets can be easily formulated and can be made easy toswallow or chew; other solid forms include granules, and bulk powders.Tablets may contain suitable binders, lubricants, diluents,disintegrating agents, coloring agents, flavoring agents, flow-inducingagents, and melting agents. Examples of suitable liquid dosage formsinclude solutions or suspensions in water, pharmaceutically acceptablefats and oils, alcohols or other organic solvents, including esters,emulsions, syrups or elixirs, suspensions, solutions and/or suspensionsreconstituted from non-effervescent granules and effervescentpreparations reconstituted from effervescent granules. Such liquiddosage forms may contain, for example, suitable solvents, preservatives,emulsifying agents, suspending agents, diluents, sweeteners, thickeners,and melting agents. Oral dosage forms optionally contain flavorants andcoloring agents. Parenteral and intravenous forms may also includeminerals and other materials to make them compatible with the type ofinjection or delivery system chosen.

Techniques and compositions for making dosage forms useful in thepresent invention are described in the following references: 7 ModernPharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979);Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel,Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976);Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company,Easton, Pa., 1985); Advances in Pharmaceutical Sciences (DavidGanderton, Trevor Jones, Eds., 1992); Advances in PharmaceuticalSciences Vol. 7. (David Ganderton, Trevor Jones, James McGinity, Eds.,1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugsand the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989);Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs andthe Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); DrugDelivery to the Gastrointestinal Tract (Ellis Horwood Books in theBiological Sciences. Series in Pharmaceutical Technology; J. G. Hardy,S. S. Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Drugs and thePharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T.Rhodes, Eds.). All of the aforementioned publications are incorporatedby reference herein.

Tablets may contain suitable binders, lubricants, disintegrating agents,coloring agents, flavoring agents, flow-inducing agents, and meltingagents. For instance, for oral administration in the dosage unit form ofa tablet or capsule, the active drug component can be combined with anoral, non-toxic, pharmaceutically acceptable, inert carrier such aslactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose,magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol,sorbitol and the like. Suitable binders include starch, gelatin, naturalsugars such as glucose or beta-lactose, corn sweeteners, natural andsynthetic gums such as acacia, tragacanth, or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes, and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride, and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

The compounds used in the method of the present invention may also beadministered in the form of liposome delivery systems, such as smallunilamellar vesicles, large unilamellar vesicles, and multilamellarvesicles. Liposomes can be formed from a variety of phospholipids suchas lecithin, sphingomyelin, proteolipids, protein-encapsulated vesiclesor from cholesterol, stearylamine, or phosphatidylcholines. Thecompounds may be administered as components of tissue-targetedemulsions.

The compounds used in the method of the present invention may also becoupled to soluble polymers as targetable drug carriers or as a prodrug.Such polymers include polyvinylpyrrolidone, pyran copolymer,polyhydroxylpropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polyglycolicacid, copolymers of polylactic and polyglycolic acid, polyepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacylates, and crosslinked or amphipathicblock copolymers of hydrogels.

Gelatin capsules may contain the active ingredient compounds andpowdered carriers, such as lactose, starch, cellulose derivatives,magnesium stearate, stearic acid, and the like. Similar diluents can beused to make compressed tablets. Both tablets and capsules can bemanufactured as immediate release products or as sustained releaseproducts to provide for continuous release of medication over a periodof hours. Compressed tablets can be sugar-coated or film-coated to maskany unpleasant taste and protect the tablet from the atmosphere, orenteric coated for selective disintegration in the gastrointestinaltract.

For oral administration in liquid dosage form, the oral drug componentsare combined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Examples ofsuitable liquid dosage forms include solutions or suspensions in water,pharmaceutically acceptable fats and oils, alcohols or other organicsolvents, including esters, emulsions, syrups or elixirs, suspensions,solutions and/or suspensions reconstituted from non-effervescentgranules and effervescent preparations reconstituted from effervescentgranules. Such liquid dosage forms may contain, for example, suitablesolvents, preservatives, emulsifying agents, suspending agents,diluents, sweeteners, thickeners, and melting agents.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance. In general, water, asuitableoil, saline, aqueous dextrose (glucose), and related sugar solutions andglycols such as propylene glycol or polyethylene glycols are suitablecarriers for parenteral solutions. Solutions for parenteraladministration preferably contain a water soluble salt of the activeingredient, suitable stabilizing agents, and if necessary, buffersubstances. Antioxidizing agents such as sodium bisulfite, sodiumsulfite, or ascorbic acid, either alone or combined, are suitablestabilizing agents. Also used are citric acid and its salts and sodiumEDTA. In addition, parenteral solutions can contain preservatives, suchas benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

The compounds used in the method of the present invention may also beadministered in intranasal form via use of suitable intranasal vehicles,or via transdermal routes, using those forms of transdermal skin patcheswell known to those of ordinary skill in that art. To be administered inthe form of a transdermal delivery system, the dosage administrationwill generally be continuous rather than intermittent throughout thedosage regimen.

Parenteral and intravenous forms may also include minerals and othermaterials such as solutol and/or ethanol to make them compatible withthe type of injection or delivery system chosen.

The compounds and compositions of the present invention can beadministered in oral dosage forms as tablets, capsules, pills, powders,granules, elixirs, tinctures, suspensions, syrups, and emulsions. Thecompounds may also be administered in intravenous (bolus or infusion),intraperitoneal, subcutaneous, or intramuscular form, or introduceddirectly, e.g. by topical administration, injection or other methods, tothe afflicted area, such as a wound, including ulcers of the skin, allusing dosage forms well known to those of ordinary skill in thepharmaceutical arts.

Specific examples of pharmaceutically acceptable carriers and excipientsthat may be used to formulate oral dosage forms of the present inventionare described in U.S. Pat. No. 3,903,297 to Robert, issued Sep. 2, 1975.Techniques and compositions for making dosage forms useful in thepresent invention are described-in the following references: 7 ModernPharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979);Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel,Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976);Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company,Easton, Pa., 1985); Advances in Pharmaceutical Sciences (DavidGanderton, Trevor Jones, Eds., 1992); Advances in PharmaceuticalSciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds.,1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugsand the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989);Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs andthe Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); DrugDelivery to the Gastrointestinal Tract (Ellis Horwood Books in theBiological Sciences. Series in Pharmaceutical Technology; J. G. Hardy,S. S. Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Drugs and thePharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T.Rhodes, Eds.). All of the aforementioned publications are incorporatedby reference herein.

The active ingredient can be administered orally in solid dosage forms,such as capsules, tablets, powders, and chewing gum; or in liquid dosageforms, such as elixirs, syrups, and suspensions, including, but notlimited to, mouthwash and toothpaste. It can also be administeredparentally, in sterile liquid dosage forms.

Solid dosage forms, such as capsules and tablets, may be enteric-coatedto prevent release of the active ingredient compounds before they reachthe small intestine. Materials that may be used as enteric coatingsinclude, but are not limited to, sugars, fatty acids, proteinaceoussubstances such as gelatin, waxes, shellac, cellulose acetate phthalate(CAP), methyl acrylate-methacrylic acid copolymers, cellulose acetatesuccinate, hydroxy propyl methyl cellulose phthalate, hydroxy propylmethyl cellulose acetate succinate (hypromellose acetate succinate),polyvinyl acetate phthalate (PVAP), and methyl methacrylate-methacrylicacid copolymers.

The compounds and compositions of the invention can be coated ontostents for temporary or permanent implantation into the cardiovascularsystem of a subject.

The compounds of the present invention can be synthesized according tomethods described in PCT International Publication No. WO 2010/132815A9. Variations on those general synthetic methods will be readilyapparent to those of ordinary skill in the art and are deemed to bewithin the scope of the present invention.

Each embodiment disclosed herein is contemplated as being applicable toeach of the other disclosed embodiments. Thus, all combinations of thevarious elements described herein are within the scope of the invention.

This invention will be better understood by reference to theExperimental Details which follow, but those skilled in the art willreadily appreciate that the specific experiments detailed are onlyillustrative of the invention as described more fully in the claimswhich follow thereafter.

EXPERIMENTAL DETAILS

Materials and Methods

All air- and moisture-insensitive reactions were carried out under anambient atmosphere, magnetically stirred, and monitored by thin layerchromatography (TLC) using Agela Technologies TLC plates pre-coated with250 μm thickness silica gel 60 F254 plates and visualized byfluorescence quenching under UV light. Flash chromatography wasperformed on SiliaFlash® Silica Gel 40-63 μm 60 Å particle size using aforced flow of eluent at 0.3-0.5 bar pressure (Still, W. C. et al. J.Org. Chem. 1978, 43, 2925-2927.). All air- and moisture-sensitivemanipulations were performed using oven-dried glassware, includingstandard Schlenk and glovebox techniques under an atmosphere ofnitrogen. Diethyl etherand THF were distilled from deep purple sodiumbenzophenone ketyl. Methylene chloride, chloroform and acetonitrile weredried over CaH₂ and distilled. Nitromethane was dried over 4 Å molecularsieves. All other chemicals were used as received. All deuteratedsolvents were purchased from Cambridge Isotope Laboratories.

NMR spectra were recorded on either a Bruker Ascend700 spectrometeroperating at 700 MHz for ¹H acquisitions and 175 MHz for ¹³Cacquisitions, a Bruker 500 Advance spectrometer operating at 500 MHz,125 MHz, and 470 MHz for ¹H, ¹³C, and ¹⁹F acquisitions, respectively, aBruker 400 Nanobay spectrometer operating at 400 MHz, 100 MHz, and 376MHz for 1H, ¹³C, and ¹⁹F acquisitions, respectively. Chemical shiftswere referenced to the residual proton solvent peaks (¹H: CDCl₃, δ 7.26;(CD₃)₂SO, δ2.50; CD₃OD, δ3.31; CD₃CN, δ1.94), solvent ¹³C signals(CDCl₃, δ77.16; (CD₃)₂SO, δ39.52; CD₃OD, δ49.00) (Fulmer, G. R. et al.Organometallics. 2010, 29, 2176-2179), dissolved or external neat PhCF₃(¹⁹F, δ−63.3 relative to CFCl₃) (Wang, X. et al. J. Am. Chem. Soc. 2013,135, 10330-10333). Signals arelisted in ppm, and multiplicity identifiedas s=singlet, br=broad, d=doublet, t=triplet, q=quartet, m=multiplet;coupling constants in Hz; integration. High-resolution mass spectra wereperformed at Mass Spectrometry Services at the Univ. of Illinois atUrbana-Champaign and were obtained using Waters Q-TOF Ultima ESI massspectrometer. Concentration under reduced pressure was performed byrotary evaporation at 25-30° C. at appropriate pressure. Purifiedcompounds were further dried under high vacuum (0.01-0.05 Torr). Yieldsrefer to purified and spectroscopically pure compounds.

Synthesis of Togni Reagent II 1-Chloro-1λ³-benzo[d] [1,2] iodaoxol-3(1)-one

The compound was prepared according to the literature procedure(Matoušek, V. et al. J. Org. Chem. 2013, 78, 6763-6768). A suspension of2-iodobenzoic acid (30.0 g, 0.121 mmol, 1.00 equiv) in MeCN (225 mL) washeated to 75° C. A solution of trichloroisocyanuric acid (9.46 g, 0.0407mol, 1.01 Cl⁺ equiv) in MeCN (45 mL) was added in one portion and thereaction mixture was heated at 75° C. for 10 min. The reaction mixturewas diluted with MeCN (150 mL) and vacuum-filtered over anoven-preheated, sintered-glass funnel and the filter cake was rinsedwith additional hot MeCN (150 mL). The filtrate was concentrated invacuo to near dryness and the resulting yellow solid was collected byfiltration and washed with cold MeCN. The mother liquor from filtrationwas partially concentrated in vacuo, giving a second crop of crystals.The combined crops were dried under vacuum overnight to afford the titlecompound as a slightly yellow crystalline solid (28.0 g, 0.0991 mol,82%). NMR Spectroscopy: ¹H NMR (400 MHz, CDCl₃, 25° C., δ): 8.27 (dd,J=7.5, 1.5 Hz, 1H), 8.22 (dd, J=8.0, 0.5 Hz, 1H), 8.00 (ddd, J=8.5, 7.2,1.6 Hz, 1H), 7.80 (td, J=7.4, 0.8 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃, 25°C., δ): 167.2, 136.8, 133.6, 132.0, 128.8, 127.0, 117.2. Thesespectroscopic data correspond to previously reported data.

(1-(trifluoromethyl)-1λ3-benzo[d][1,2]iodaoxol-3(1H)-one)

Potassium acetate (10.8 g, 0.110 mol, 2.00 equiv) was dried under vacuumat 150° C. for 30 min and then cooled to rt.1-chloro-1λ3-benzo[d][1,2]iodaoxol-3(1H)-one (15.6 g, 0.0551 mol, 1.00equiv) and MeCN (155 mL) were added and the reaction mixture was stirredat 75° C. for 2 h. The reaction mixture was cooled to rt. TMSCF₃ (8.97mL, 0.0607 mol, 1.10 equiv) was added in one portion and the reactionmixture was stirred at rt for 15 h. MeCN (100 mL) was then added and thebrown reaction mixture was heated to 75° C. and the hot reaction mixturewas filtered through a pad of Celite, concentrated to about 50 mL endvolume, and cooled to −20° C. The crystals were filtered off, washedwith cold (−20° C.) MeCN (50 mL) and dried under vacuum. The motherliquor was again concentrated to approximately 15 mL end volume andcooled to −20° C. The crystals were filtered off and washed with a cold(−20° C.) MeCN (10 mL). Both crystalline fractions were dried under ahigh vacuum to afford the title compound as a white crystalline solid(14.6 g, 0.0463 mol, 84% yield). NMR Spectroscopy: ¹H NMR (500 MHz,CDCl₃, 25° C., δ): 8.48 (dd, J=7.2, 1.7 Hz, 1H), 7.85-7.76 (m, 3H). ¹³CNMR (175 MHz, CDCl₃, 25° C., δ): 165.9, 135.9, 133.9, 132.1, 132.0,127.3 (q, J=2.5 Hz), 114.9, 107.3 (q, J=378.8 Hz). ¹⁹F NMR (376 MHz,CDCl₃, 25° C., δ): −34.2 (s). These spectroscopic data correspond topreviously reported data.

Preparation of Starting Hydroxylamines General Procedure for theSynthesis of N-aryl-N-hydroxylamines

Under N₂ atmosphere, a suspension of aryl nitro compound (1.00 equiv)and Rh/C (5 mol %) in THF (0.20M) was cooled to 0° C. Hydrazinemonohydrate (1.20 equiv) was added dropwise. The reaction mixturestirred at 0° C. until the TLC analysis indicated a complete consumptionof the starting material. The reaction mixture was filtered through ashort pad of celite and concentrated in vacuo. The residue was useddirectly for the next step without further purification unless otherwisestated.

General Procedure for the Synthesis of Protected N-aryl-N-hydroxylamines

To a stirred suspension of N-aryl-N-hydroxylamine (1.00 equiv) andNaHCO₃ (1.20 equiv) in Et₂O (0.20M) at 0° C. under N₂ was slowly added asolution of protecting group precursor (1.20 equiv) in Et₂O (0.24 M) viaa syringe pump (at a rate of 10 mL/h). The reaction was stirred at 0° C.until the TLC analysis indicated a complete consumption of the startingmaterial. The reaction mixture was filtered through a short pad ofcelite and concentrated in vacuo. The residue was purified bychromatography on silica gel.

N-Phenyl-N-hydroxylamine (S1a)

Under N₂ atmosphere, a suspension of nitrobenzene (1.00 g, 8.10 mmol,1.00 equiv) and 5% Rh/C (40.5 mg, 0.30 mol % Rh) in THF (25.0 mL, 0.324M) was cooled to 0° C. Hydrazine monohydrate (0.487 g, 9.72 mmol, 1.20equiv) was added dropwise. The reaction mixture stirred at 0° C. for 1 hand then slowly warmed up to rt and stirred at rt for 4 h. The reactionmixture was filtered through a short pad of celite and concentrated invacuo. Recrystallization from CH₂Cl₂/hexanes at −20° C. afforded thetitle compound as a white solid (0.740 g, 6.78 mmol, 84% yield).R_(f)=0.25 (hexanes/EtOAc 1:1 (v/v)). NMR Spectroscopy: 1H NMR (500 MHz,(CD₃)₂SO, δ): 8.25 (s, 1H), 8.21 (s, 1H), 7.14 (t, J=7.9 Hz, 2H), 6.81(d, J=7.9 Hz, 2H), 6.72 (t, J=7.9 Hz, 1H). ₁₃C NMR (125 MHz, (CD₃)₂SO,δ): 152.1, 128.4, 119.2, 112.9.

4-(Hydroxyamino)benzonitrile (S1b)

Under N₂ atmosphere, a suspension of 4-nitrobenzonitrile (2.00 g, 13.5mmol, 1.00 equiv) and 5% Rh/C (77.6 mg, 0.30 mol % Rh) in THF (40.0 mL,0.338 M) was cooled to 0° C. Hydrazine monohydrate (0.810 g, 16.2 mmol,1.20 equiv) was added dropwise. The reaction mixture stirred at 0° C.for 1 h and then slowly warmed up to rt and stirred at rt for 1 h. Thereaction mixture was filtered through a short pad of celite andconcentrated in vacuo to afford the title compound as a yellow solid(1.80 g, 13.4 mmol, 99% yield). R_(f) ⁼0.14 (hexanes/EtOAc 5:1 (v/v)).NMR Spectroscopy: ¹H NMR (400 MHz, (CD₃)₂SO, δ): 9.10 (s, 1H), 8.76 (s,1H), 7.57-7.52 (m, 2H), 7.85 (d, J=8.6 Hz, 2H). ₁₃C NMR (100 MHz,(CD₃)₂SO, δ): 155.4, 133.1, 120.1, 111.8, 90.1.

1-(4-(Hydroxyamino)phenyl)ethan-1-one (S1c)

Under N₂ atmosphere, a suspension of1-(4-nitrophenyl)ethan-1-one (3.00g, 18.2 mmol, 1.00 equiv) and 5% Rh/C (104 mg, 0.30 mol % Rh) in THF(90.0 mL, 0.202 M) was cooled to 0° C. Hydrazine monohydrate (1.09 g,21.8 mmol, 1.20 equiv) was added dropwise. The reaction mixture stirredat 000° C. for 3.5 h. The reaction mixture was filtered through a shortpad of celite and concentrated in vacuo to afford the title compound asa yellow solid (2.80 g, 18.5 mmol, quant yield). R_(f)=0.27(hexanes/EtOAc 5:1 (v/v)). NMR Spectroscopy: ¹H NMR (400 MHz, (CD₃)₂SO,δ): 8.99 (s, 1H), 8.67 (s, 1H), 7.79 (d, J=8.7 Hz, 2H), 6.82 (d, J=8.7Hz, 2H), 2.44 (s, 3H). ₁₃C NMR (100 MHz, (CD₃)₂SO, δ): 195.6, 155.9,129.8, 127.7, 110.9, 26.1.

4-(Hydroxyamino)-N,N-dimethylbenzamide (S1d)

Under N₂ atmosphere, a suspension of N,N-dimethyl-4-nitrobenzamide (1.00g, 6.53 mmol, 1.00 equiv) and 5% Rh/C (50.0 mg, 0.30 mol % Rh) in THF(25.0 mL, 0.261 M) was cooled to 0° C. Hydrazine monohydrate (1.09 g,21.8 mmol, 1.20 equiv) was added dropwise. The reaction mixture stirredat 0° C. for 2 h. The reaction mixture was filtered through a short padof celite. The celite was washed with EtOAc and the combined organiclayers were concentrated in vacuo to afford the title compound as awhite solid (0.860 g, 4.77 mmol, 73% yield). R_(f)=0.22 (hexanes/EtOAc1:4 (v/v)). NMR Spectroscopy: 1H NMR (700 MHz, CD₃OD, 25° C., δ): 7.32(d, J=8.5 Hz, 2H), 6.97 (d, J=8.5 Hz, 2H), 3.06 (s, 6H). ¹³C NMR (175MHz, CD₃OD, 25° C., δ): 174.3, 154.9, 129.4, 128.2, 113.7, 40.3, 35.9.Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₉H₁₃N₂O₂ ([M+H]₊),181.0977, found, 181.0982.

N-(4-Fluorophenyl)hydroxylamine (S1e)

Under N₂ atmosphere, a suspension of 1-fluoro-4-nitrobenzene (2.00 g,14.2 mmol, 1.00 equiv) and 5% Rh/C (81.4 mg, 0.30 mol % Rh) in THF (40.0mL, 0.355 M) was cooled to 0° C. Hydrazine monohydrate (0.810 g, 16.2mmol, 1.20 equiv) was added dropwise. The reaction mixture stirred at 0°C. for 2 h. The reaction mixture was filtered through a short pad ofcelite and concentrated in vacuo to afford the title compound as ayellow solid (1.81 g, 14.2 mmol, quant yield). R_(f) ⁼0.29(hexanes/EtOAc 4:1 (v/v)). NMR Spectroscopy: ¹H NMR (500 MHz, (CD₃)₂SO,δ): 8.33 (d, J=2.4 Hz, 1H), 8.19 (s, 1H), 7.02-6.97 (m, 2H), 6.85-6.81(m, 2H). ¹³C NMR (125 MHz, (CD₃)₂SO, δ): 156.2 (d, J=232.7 Hz), 148.5(d, J=1.5 Hz), 114.8 (d, J=22.1 Hz), 114.2 (d, J=7.8 Hz). ¹⁹F NMR (376MHz, (CD₃)₂SO, 25° C., δ): −127.6 (s). Mass Spectrometry: HRMS (ESI-TOF)(m/z): calcd for C₆H₇NOF ([M+H]₊), 128.0512, found, 128.0513.

N-(4-Chlorophenyl)hydroxylamine (S1f)

Under N₂ atmosphere, a suspension of1-chloro-4-nitrobenzene (2.00 g,12.7 mmol, 1.00 equiv) and 5% Rh/C (72.9 mg, 0.30 mol % Rh) in THF (40.0mL, 0.318 M) was cooled to 0° C. Hydrazine monohydrate (0.762 g, 15.2mmol, 1.20 equiv) was added dropwise. The reaction mixture stirred at 0°C. for 2.5 h. The reaction mixture was filtered through a short pad ofcelite and concentrated in vacuo to afford the title compound as ayellow solid (1.72 g, 12.0 mmol, 95% yield). R_(f)=0.27 (hexanes/EtOAc5:1 (v/v)). NMR Spectroscopy: ¹H NMR (500 MHz, (CD₃)₂SO, δ): 8.43 (d,J=2.2 Hz, 1H), 8.40 (s, 1H), 7.19 (d, J=8.8 Hz, 2H), 6.87-6.83 (m, 2H).¹³C NMR (125 MHz, (CD₃)₂SO, δ): 151.0, 128.3, 122.6, 114.4.

N-(4-Bromophenyl)hydroxylamine (S1g)

Under N₂ atmosphere, a suspension of 1-bromo-4-nitrobenzene (3.00 g,14.9 mmol, 1.00 equiv) and 5% Rh/C (85.3 mg, 0.30 mol % Rh) in THF (100mL, 0.149 M) was cooled to 0° C. Hydrazine monohydrate (0.892 g, 16.2mmol, 1.20 equiv) was added dropwise. The reaction mixture stirred at 0°C. for 2.5 h. The reaction mixture was filtered through a short pad ofcelite and concentrated in vacuo to afford the title compound as a brownsolid (2.78 g, 14.8 mmol, 99% yield). R_(f)=0.30 (hexanes/EtOAc 5:1(v/v)). NMR Spectroscopy: ¹H NMR (500 MHz, (CD₃)₂SO, δ): 8.42 (s, 1H),8.40 (s, 1H), 7.30 (d, J=8.8 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H). ¹³C NMR(125 MHz, (CD₃)₂SO, δ): 151.4, 131.1, 114.8, 110.1. Mass Spectrometry:HRMS (ESI-TOF) (m/z): calcd for C₆H₇NOBr ([M+H]₊), 187.9711, found,187.9714.

N-(4-Iodophenyl)hydroxylamine (S1h)

Under N₂ atmosphere, a suspension of1-iodo-4-nitrobenzene (2.00 g, 8.03mmol, 1.00 equiv) and 5% Rh/C (46.1 mg, 0.30 mol % Rh) in THF (30.0 mL,0.268 M) was cooled to 0° C. Hydrazine monohydrate (0.482 g, 9.64 mmol,1.20 equiv) was added dropwise. The reaction mixture stirred at 000° C.for 2 h. The reaction mixture was filtered through a short pad of celiteand concentrated in vacuo. Recrystallization from CH₂Cl₂/hexanes at −20°C. afforded the title compound as a yellow solid (1.20 g, 5.11 mmol, 64%yield). R_(f)=0.26 (hexanes/EtOAc 5:1 (v/v)). NMR Spectroscopy: ¹H NMR(500 MHz, (CD₃)₂SO, δ): 8.41 (s, 2H), 7.46 (d, J=2.7 Hz, 1H), 7.44 (d,J=2.7 Hz, 1H), 6.67 (d, J=2.6 Hz, 1H), 6.65 (d, J=2.6 Hz, 1H). ¹³C NMR(125 MHz, (CD₃)₂SO, δ): 152.4, 137.3, 115.8, 81.1.

N-(3-Fluorophenyl)hydroxylamine (S1i)

Under N₂ atmosphere, a suspension of 1-fluoro-3-nitrobenzene (1.00 g,7.09 mmol, 1.00 equiv) and 5% Rh/C (50.0 mg, 0.30 mol % Rh) in THF (25.0mL, 0.284 M) was cooled to 0° C. Hydrazine monohydrate (0.390 g, 7.80mmol, 1.10 equiv) was added dropwise. The reaction mixture stirred at 0°C. for 1 h. The reaction mixture was filtered through a short pad ofcelite. The celite was washed with EtOAc and the combined organic layerswere concentrated in vacuo to afford the title compound as a white solid(0.870 g, 7.12 mmol, quant yield). R_(f)=0.28 (hexanes/EtOAc 4:1 (v/v)).¹H NMR (400 MHz, (CD₃)₂SO, δ): 8.50 (s, 1H), 8.45 (d, J=2.1 Hz, 1H),7.17-7.14 (m, 1H), 6.61-6.58 (m, 2H), 6.50-6.48 (m, 1H). ¹³C NMR (100MHz, (CD₃)₂SO, δ): 163.0 (d, J=238.8 Hz), 154.4 (d, J=10.2 Hz), 130.0(d, J=9.6 Hz), 108.7 (d, J=2.3 Hz), 105.1 (d, J=21.4 Hz), 99.3 (d,J=25.5 Hz). ¹⁹F NMR (376 MHz, (CD₃)₂SO, 25° C., δ): −117.3 (s). MassSpectrometry: HRMS (ESI-TOF) (m/z): calcd for C₆H₇NOF ([M+H]₊),128.0512, found, 128.0513.

N-(2-Bromophenyl)hydroxylamine (S1j)

Under N₂ atmosphere, a suspension of1-bromo-2-nitrobenzene (1.00 g, 4.95mmol, 1.00 equiv) and 5% Rh/C (28.4 mg, 0.30 mol % Rh) in THF (50.0 mL,0.0990M) was cooled to 0° C. Hydrazine monohydrate (0.297 g, 5.94 mmol,1.20 equiv) was added dropwise. The reaction mixture stirred at 0° C.for 2.5 h. The reaction mixture was filtered through a short pad ofcelite, the celite was washed with EtOAc and the combined organic layerswere concentrated in vacuo and solidified upon standing at −20° C. toafford the title compound as a yellow solid (0.930 g, 4.95 mmol, quantyield). R_(f)=0.21 (hexanes/EtOAc 1:1 (v/v)). NMR Spectroscopy: ¹H NMR(500 MHz, (CD₃)₂SO, δ): 8.58 (m, 1H), 7.98 (s, 1H), 7.40 (dd, J=7.8,0.85 Hz, 1H), 7.28-7.24 (m, 1H), 7.18-7.15 (m, 1H), 6.74-6.70 (m, 1H).¹³C NMR (125 MHz, (CD₃)₂SO, δ): 148.6, 131.8, 128.2, 120.7, 114.6,106.7. Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₆H₇NOBr([M+H]₊), 187.9711, found, 187.9710.

N-(3-Methoxy-5-(trifluoromethyl)phenyl)hydroxylamine (S1k)

Under N₂ atmosphere, a suspension of1-methoxy-3-nitro-5-(trifluoromethyl)benzene (1.00 g, 4.50 mmol, 1.00equiv) and 5% Rh/C (25.9 mg, 0.30 mol % Rh) in THF (15.0 mL, 0.300 M)was cooled to 0° C. Hydrazine monohydrate (0.270 g, 5.40 mmol, 1.20equiv) was added dropwise. The reaction mixture stirred at 0° C. for 1 hand then slowly warmed up to rt and stirred at rt for 1 h. The reactionmixture was filtered through a short pad of celite, the celite waswashed with EtOAc and the combined organic layers were concentrated invacuo to afford the title compound as a yellow solid (0.960 g, 4.60mmol, quant yield). R_(f)=0.29 (hexanes/EtOAc 4:1 (v/v)). NMRSpectroscopy: ¹H NMR (400 MHz, (CD₃)₂SO, δ): 8.65 (s, 1H), 8.58 (br. s,1H), 6.68 (s, 1H), 6.61 (s, 1H), 6.57 (s, 1H), 3.76 (s, 3H). ¹³C NMR(100 MHz, (CD₃)₂SO, δ): 160.3, 154.3, 130.4 (q, J=31.0 Hz), 124.2 (q,J=271.0 Hz), 101.6 (q, J=4.1 Hz), 101.3, 101.0 (q, J=3.9 Hz), 55.3. ¹⁹FNMR (376 MHz, (CD₃)₂SO, 25° C., δ): −63.6 (s). Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₈H₉NO₂F₃ ([M+H]₊), 208.0585, found,208.0579.

N-(3-(Trifluoromethyl)phenyl)hydroxylamine (S1l)

Under N₂ atmosphere, a suspension of 1-nitro-3-(trifluoromethyl)benzene(1.00 g, 5.21 mmol, 1.00 equiv) and 5% Rh/C (50 mg, 0.30 mol % Rh) inTHF (25.0 mL, 0.208 M) was cooled to 0° C. Hydrazine monohydrate (0.314g, 5.73 mmol, 1.10 equiv) was added dropwise. The reaction mixturestirred at 0° C. for 2 h. The reaction mixture was filtered through ashort pad of celite, the celite was washed with EtOAc and the combinedorganic layers were concentrated in vacuo to afford the title compoundas a yellow solid (0.880 g, 4.97 mmol, 95% yield). R_(f)=0.30(hexanes/EtOAc 4:1 (v/v)). ¹H NMR (400 MHz, (CD₃)₂SO, δ): 8.66 (s, 1H),8.58 (s, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.09 (s, 1H), 7.07-7.03 (m, 2H).¹³C NMR (175 MHz, (CD₃)₂SO, δ): 152.7, 129.4 (q, J=30.6 Hz), 124.4 (q,J=270.6 Hz), 116.3, 115.2 (d, J=3.8 Hz), 111.9, 108.5 (q, J=4.0 Hz). ¹⁹FNMR (376 MHz, (CD₃)₂SO, 25° C., δ): −63.4 (s).

N-(3-Methoxyphenyl)hydroxylamine (S1m)

Under N₂ atmosphere, a suspension of 1-methoxy-3-nitrobenzene (1.00 g,6.53 mmol, 1.00 equiv) and 5% Rh/C (50 mg, 0.30 mol % Rh) in THF (25.0mL, 0.261 M) was cooled to 0° C. Hydrazine monohydrate (0.360 g, 7.19mmol, 1.10 equiv) was added dropwise. The reaction mixture stirred at 0°C. for 2 h. The reaction mixture was filtered through a short pad ofcelite, the celite was washed with EtOAc and the combined organic layerswere concentrated in vacuo to afford the title compound as a white solid(0.890 g, 6.40 mmol, 98% yield). R_(f)=0.47 (hexanes/EtOAc 3:2 (v/v)).NMR Spectroscopy: ¹H NMR (500 MHz, (CD₃)₂SO, 25° C., δ): 8.26 (d, J=2.2Hz, 1H), 8.23 (s, 1H), 7.04 (t, J=8.0 Hz, 1H), 6.38-6.41 (m, 2H), 6.30(dd, J=8.0, 2.3 Hz, 1H), 3.68 (s, 3H). ₁₃C NMR (125 MHz, (CD₃)₂SO, 25°C., δ): 159.8, 153.5, 129.1, 105.5, 104.6, 98.5, 54.6. MassSpectrometry: HRMS (ESI-TOF) (m/z): calcd for C₇H₁₀NO₂ ([M+H]₊),140.0712, found, 140.0714.

Methyl 3-(hydroxyamino)benzoate (S1n)

Under N₂ atmosphere, a suspension of methyl 3-nitrobenzoate (2.00 g,11.0 mmol, 1.00 equiv) and 5% Rh/C (63.0 mg, 0.30 mol % Rh) in THF (40.0mL, 0.275 M) was cooled to 0° C. Hydrazine monohydrate (0.663 g, 13.3mmol, 1.20 equiv) was added dropwise. The reaction mixture stirred at 0°C. for 2.5 h. The reaction mixture was filtered through a short pad ofcelite, the celite was washed with EtOAc and the combined organic layerswere concentrated in vacuo to afford the title compound as a lightyellow solid (1.82 g, 10.9 mmol, 99% yield). R_(f)=0.19 (hexanes/EtOAc4:1 (v/v)). NMR Spectroscopy: ¹H NMR (500 MHz, (CD₃)₂SO, δ): 8.51 (s,1H), 8.49 (d, J=2.1 Hz, 1H), 7.45 (s, 1H), 7.35-7.28 (m, 2H), 7.07-7.04(m, 1H), 3.82 (s, 3H). ¹³C NMR (125 MHz, (CD₃)₂SO, δ): 166.6, 152.4,130.0, 128.9, 119.9, 117.5, 113.2, 52.1. Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₈H₁₀NO₃ ([M+H]₊), 168.0661, found, 168.0666.

N-(2-Chloro-5-(trifluoromethyl)phenyl)hydroxylamine (S1o)

Under N₂ atmosphere, a suspensionof1-chloro-2-nitro-4-(trifluoromethyl)benzene (1.00 g, 4.43 mmol, 1.00equiv) and 5% Rh/C (25.5 mg, 0.30 mol % Rh) in THF (45.0 mL, 0.0984 M)was cooled to 0° C. Hydrazine monohydrate (0.266 g, 5.32 mmol, 1.20equiv) was added dropwise. The reaction mixture stirred at 0° C. for 1.5h. The reaction mixture was filtered through a short pad of celite, thecelite was washed with EtOAc and the combined organic layers wereconcentrated in vacuo and solidified upon standing at −20° C. to affordthe title compound as a yellow solid (0.930 g, 4.40 mmol, 99% yield).R_(f)=0.31 (hexanes/EtOAc 1:1 (v/v)). NMR Spectroscopy: ¹H NMR (500 MHz,(CD₃)₂SO, δ): 8.86 (s, 1H), 8.74 (s, 1H), 7.49 (d, J=8.2 Hz, 1H), 7.36(d, J=1.8 Hz, 1H), 7.10-7.08 (m, 1H). ¹³C NMR (125 MHz, (CD₃)₂SO, δ):148.4, 129.8, 128.5 (q, J=31.6 Hz), 124.1 (q, J=270.6 Hz), 120.7, 115.9(m), 109.7 (m). ¹⁹F NMR (376 MHz, (CD₃)₂SO, 25° C., δ): −63.5 (s). MassSpectrometry: HRMS (ESI-TOF) (m/z): calcd for C₇H₆NOClF₃ ([M+H]₊),212.0090, found, 212.0092.

3-benzyl-8-chloro-7-(hydroxyamino) quinazolin-4 (3H)-one (S1p)

Under N₂ atmosphere, a suspension of3-benzyl-8-chloro-7-nitroquinazolin-4(3H)-one (1.05 g, 3.33 mmol, 1.00equiv) and 5% Rh/C (50.0 mg, 0.30 mol % Rh) in THF (20 mL, 0.167 M) wascooled to 0° C. Hydrazine monohydrate (0.183 g, 3.66 mmol, 1.20 equiv)was added dropwise. The reaction mixture stirred at 0° C. for 4 h. Thereaction mixture was filtered through a short pad of celite andconcentrated in vacuo to afford the title compound as a yellow solid(0.950 g, 3.15 mmol, 95% yield). R_(f)=0.22 (hexanes/EtOAc 4:1 (v/v)).NMR Spectroscopy: ¹H NMR (700 MHz, (CD₃)₂SO, δ): 8.86 (s, 1H), 8.74 (s,1H), 8.40 (s, 1H), 7.76 (s, 1H), 7.66 (s, 1H), 7.35-7.34 (m, 4H),7.30-7.28 (m, 1H), 5.18 (s, 21H). ¹³C NMR (175 MHz, (CD₃)₂SO, δ): 159.7,146.9, 145.9, 141.3, 136.9, 128.6, 127.7, 127.6, 127.2, 124.8, 121.4,108.0, 48.8. Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for.C₁₅H₁₃N₃O₂Cl ([M+H]₊), 302.0696, found, 302.0690.

Methyl 4-(hydroxyamino)benzoate (S1q)

Under N₂ atmosphere, a suspension of methyl 4-nitrobenzoate (5.00 g,27.6 mmol, 1.00 equiv) and 5% Rh/C (159 mg, 0.30 mol % Rh) in THF (300mL, 0.0920 M) was cooled to 0° C. Hydrazine monohydrate (1.52 g, 30.4mmol, 1.20 equiv) was added dropwise. The reaction mixture stirred at 0°C. for 5 h. The reaction mixture was filtered through a short pad ofcelite, the celite was washed with EtOAc and the combined organic layerswere concentrated in vacuo to afford the title compound as a yellowsolid (4.62 g, 27.6 mmol, quant yield). R_(f)=0.23 (hexanes/EtOAc 4:1(v/v)). NMR Spectroscopy: ¹H NMR (500 MHz, (CD₃)₂SO, δ): 8.95 (s, 1H),8.64 (d, J=1.5 Hz, 1H), 7.76 (d, J=8.7 Hz, 2H), 6.82 (d, J=8.7 Hz, 2H),3.77 (s, 3H). ¹³C NMR (125 MHz, (CD₃)₂SO, δ): 166.2, 156.0, 130.4,119.1, 111.2, 51.4. Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd forC₈H₁₀NO₃ ([M+H]₊), 168.0661, found, 168.0667.

N-(p-Tolyl)hydroxylamine (S1u)

Under N₂ atmosphere, a suspension of 1-methyl-4-nitrobenzene (2.50 g,18.3 mmol, 1.00 equiv) and 5% Rh/C (104.8 mg, 0.30 mol % Rh) in THF(91.0 mL, 0.200 M) was cooled to 0° C. Hydrazine monohydrate (1.11 g,21.9 mmol, 1.20 equiv) was added dropwise. The reaction mixture wasstirred at 0° C. for 2.5 h, filtered through a short pad of celite andconcentrated in vacuo to afford the title compound as a brown solid(2.25 g, 18.3 mmol, quant yield). R_(f)=0.20 (hexanes/EtOAc 4:1 (v/v)).NMR Spectroscopy: ¹H NMR (400 MHz, (CD₃)₂SO, δ): 8.20 (d, J=2.3 Hz, 1H),8.06 (s, 1H), 6.96 (d, J=8.2 Hz, 2H), 6.74 (d, J=8.2 Hz, 2H), 2.19 (s,1H). ¹³C NMR (100 MHz, (CD₃)₂SO, δ): 149.7, 128.8, 127.8, 113.3, 20.2.Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₇H₁₀NO ([M+H]₊),124.0762, found, 124.0761.

Methyl (R)-2-acetamido-3-(4-(hydroxyamino)phenyl)propanoate (S1v)

Under N₂ atmosphere, a suspension of methyl(R)-2-acetamido-3-(4-nitrophenyl)propanoate (1.00 g, 3.76 mmol, 1.00equiv) and 5% Rh/C (21.6 mg, 0.30 mol % Rh) in THF (40 mL, 0.094 M) wascooled to 0° C. Hydrazine monohydrate (0.226 g, 4.51 mmol, 1.20 equiv)was added dropwise. The reaction mixture stirred at 0° C. for 8 h,filtered through a short pad of celite and concentrated in vacuo toafford the title compound as a yellow solid (0.950 g, 3.77 mmol, quantyield). R_(f)=0.42 (EtOAc). NMR Spectroscopy: ¹H NMR (500 MHz, (CD₃)₂SO,δ): 8.14 (s, 1H), 8.12 (s, 1H), 8.05 (s, 1H), 7.00 (d, J=8.3 Hz, 2H),6.76 (d, J=8.3 Hz, 2H), 4.39 (dd, J=8.3, 14.1 Hz, 1H), 3.58 (s, 3H),2.89 (dd, J=8.8, 14.1 Hz, 1H), 2.77 (dd, J=8.8, 14.1 Hz, 1H), 1.80 (s,3H). ¹³C NMR (125 MHz, (CD₃)₂SO, δ): 172.1, 169.0, 150.5, 128.8, 127.6,112.9, 53.8, 51.4, 36.2, 22.1.

N-(Quinolin-8-yl)hydroxylamine (S1w)

Under N₂ atmosphere, a suspension of 8-nitroquinoline (1.00 g, 5.74mmol, 1.00 equiv) and 5% Rh/C (32.9 mg, 0.30 mol % Rh) in THF (60 mL,0.096 M) was cooled to 0° C. Hydrazine monohydrate (0.345 g, 6.89 mmol,1.20 equiv) was added dropwise. The reaction mixture was stirred at 0°C. for 4 h, filtered through a short pad of celite and concentrated invacuo to afford the title compound as a brown solid (0.910 g, 5.68 mmol,99% yield). R_(f)=0.50 (hexanes/EtOAc 5:1 (v/v)). NMR Spectroscopy: ¹HNMR (500 MHz, (CD₃)₂SO, δ): 8.78-8.75 (m, 2H), 8.68 (s, 1H), 8.26 (d,J=8.2 Hz, 1H), 7.51 (dd, J=4.1, 8.2 Hz, 1H), 7.47 (t, J=7.9 Hz, 1H),7.30 (d, J=8.2 Hz, 1H), 7.22 (d, J=7.9 Hz, 1H). ¹³C NMR (125 MHz,(CD₃)₂SO, δ): 147.7, 147.3, 137.1, 135.9, 127.7, 127.3, 121.6, 117.2,109.3. Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₉H₉N₂₀([M+H]₊), 161.0715, found, 161.0721.

N-(1-(phenylsulfonyl)-1H-indol-5-yl)hydroxylamine (S1x)

Under N₂ atmosphere, a suspension of5-nitro-1-(phenylsulfonyl)-1H-indole (1.00 g, 3.31 mmol, 1.00 equiv) and5% Rh/C (19.0 mg, 0.30 mol % Rh) in THF (35 mL, 0.094 M) was cooled to0° C. Hydrazine monohydrate (0.199 g, 3.97 mmol, 1.20 equiv) was addeddropwise. The reaction mixture stirred at 0° C. for 1 h, filteredthrough a short pad of celite and concentrated in vacuo to afford thetitle compound as a yellow solid (0.950 g, 3.29 mmol, quant yield).R_(f)=0.27 (hexanes/EtOAc 2:1 (v/v)). ¹H NMR (500 MHz, (CD₃)₂SO, δ):8.33 (d, J=2.1 Hz, 1H), 8.25 (s, 1H), 7.92 (s, 1H), 7.90 (s, 1H), 7.74(d, J=8.9 Hz, 1H), 7.67-7.63 (m, 2H), 7.58-7.54 (m, 2H), 7.02 (d, J=1.5Hz, 1H), 6.85 (dd, J=1.9, 8.9 Hz, 1H), 6.72 (d, J=3.6 Hz, 1H). ¹³C NMR(125 MHz, (CD₃)₂SO, δ): 148.8, 137.1, 134.4, 131.2, 129.8, 128.6, 127.1,126.5, 113.2, 112.2, 110.0, 104.3. Mass Spectrometry: HRMS (ESI-TOF)(m/z): calcd for C₁₄H₁₃N₂O₃S ([M+H]₊), 289.0647, found, 289.0645.

N-Hydroxy-N-phenylacetamide (1a)

To a stirred suspension of N-phenylhydroxylamine (0.500 g, 4.58 mmol,1.00 equiv) and NaHCO₃ (0.462 g, 5.50 mmol, 1.20 equiv) in Et₂O (15.0mL, 0.305 M) at 0° C. under N₂ was slowly added a solution of acetylchloride (0.432 g, 5.50 mmol, 1.20 equiv) in Et₂O (15.0 mL, 0.367 M) viaa syringe pump (at a rate of 10.0 mL/h). After the addition wascomplete, the reaction mixture was filtered through a short pad ofcelite and the celite was washed with EtOAc. The combined organic layerswere washed with water, dried with MgSO₄, filtered, and concentrated invacuo.

The residue was purified by chromatography on silica gel, eluting withhexanes:EtOAc (4:1 to 3:2 (v/v)), to afford the title compound as awhite solid (0.590 g, 3.90 mmol, 86% yield). R_(f)=0.27 (hexanes/EtOAc3:2 (v/v)). NMR Spectroscopy: ¹H NMR (500 MHz, (CD₃)₂SO, δ): 10.61 (s,1H), 7.59 (d, J=6.0 Hz, 2H), 7.35 (t, J=6.0 Hz, 2H), 7.13 (t, J=6.0 Hz,1H), 2.18 (s, 3H). ¹³C NMR (125 MHz, (CD₃)₂SO, δ): 169.9, 141.7, 128.4,124.7, 120.3, 22.5.

N-(4-Cyanophenyl)-N-hydroxyacetamide (1b)

To a stirred suspension of 4-(hydroxyamino)benzonitrile (0.500 g, 3.73mmol, 1.00 equiv) and NaHCO₃ (0.380 g, 4.47 mmol, 1.20 equiv) in Et₂O(25.0 mL, 0.149 M) at 0° C. under N₂ was slowly added a solution ofacetyl chloride (0.350 g, 4.47 mmol, 1.20 equiv) in Et₂O (10.0 mL, 0.447M) via a syringe pump (at a rate of 10.0 mL/h). After the addition wascomplete, the reaction mixture was filtered through a short pad ofcelite and the celite was washed with EtOAc. The organic layers werecombined, concentrated in vacuo. Recrystallization from Et₂O/hexanesafforded the title compound as a light pink solid (0.510 g, 2.89 mmol,78% yield). R_(f)=0.32 (hexanes/EtOAc 1:1 (v/v)). NMR Spectroscopy: 1HNMR (400 MHz, (CD₃)₂SO, δ): 10.92 (s, 1H), 7.88 (d, J=9.0 Hz, 2H), 7.82(d, J=9.0 Hz, 2H), 2.27 (s, 3H). ¹³C NMR (100 MHz, (CD₃)₂SO, δ): 171.1,145.1, 132.9, 118.9, 118.8, 105.7, 22.9. Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₉H₉N₂O₂ ([M+H]₊), 177.0664, found, 177.0665.

N-(4-Acetylphenyl)-N-hydroxyacetamide (1c)

To a stirred suspension of 1-(4-(hydroxyamino)phenyl)ethan-1-one (S1c)(0.200 g, 1.32 mmol, 1.00 equiv) and NaHCO₃ (0.130 g, 1.59 mmol, 1.20equiv) in Et₂O (10.0 mL, 0.132 M) at 0° C. under N₂ was slowly added asolution of acetyl chloride (0.130 g, 1.59 mmol, 1.20 equiv) in Et₂O(5.00 mL, 0.318 M) via a syringe pump (at a rate of 10.0 mL/h). Afterthe addition was complete, the reaction mixture was filtered through ashort pad of celite and the celite was washed with EtOAc. The organiclayers were combined and concentrated in vacuo. The residue was purifiedby chromatography on silica gel, eluting with hexanes:EtOAc (2:1 to 1:1(v/v)), to afford the title compound as a white solid (0.230 g, 1.19mmol, 91% yield). R_(f)=0.13 (hexanes/EtOAc 2:1 (v/v)). NMRSpectroscopy: ¹H NMR (400 MHz, (CD₃)₂SO, δ): 10.84 (s, 1H), 7.96 (d,J=8.9 Hz, 2H), 7.82 (d, J=8.9 Hz, 2H), 2.54 (s, 3H), 2.27 (s, 3H). ¹³CNMR (100 MHz, (CD₃)₂SO, δ): 196.6, 170.8, 145.3, 132.2, 128.9, 118.3,26.5, 22.9. Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₁₀H₁₂NO₃([M+H]₊), 194.0817, found, 194.0820.

4-(N-Hydroxyacetamido)-N,N-dimethylbenzamide (1d)

To a stirred suspension of 4-(hydroxyamino)-N,N-dimethylbenzamide (S1d)(0.800 g, 3.93 mmol, 1.00 equiv) and NaHCO₃ (0.400 g, 4.72 mmol, 1.20equiv) in Et₂O (15.0 mL, 0.262 M) at 0° C. under N₂ was slowly added asolution of acetyl chloride (0.370 g, 4.72 mmol, 1.20 equiv) in Et₂O(20.0 mL, 0.236 M) via a syringe pump (at a rate of 10.0 mL/h). Afterthe addition was complete, water was added, and the reaction mixture wasfiltered. The solid was washed with Et₂O, dried under vacuum at 40° C.for 2 h to afford the title compound as yellow solid (0.570 g, 2.56mmol, 39% yield). R_(f)=0.11 (hexanes/EtOAc 2:1 (v/v)). ¹H NMR (500 MHz,(CD₃)₂SO, δ): 10.71 (s, 1H), 7.70 (d, J=7.5 Hz, 2H), 7.41 (d, J=7.5 Hz,2H), 2.94 (s, 6H), 2.24 (s, 3H). ¹³C NMR (125 MHz, (CD₃)₂SO, δ): 170.2,169.7, 142.3, 132.0, 127.5, 118.9, 34.9, 22.6. Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₁₁H₁₅N₂O₃ ([M+H]₊), 223.1083, found,223.1084.

N-(4-Fluorophenyl)-N-hydroxyacetamide (1e)

To a stirred suspension of N-(4-fluorophenyl)hydroxylamine (S1e) (0.500g, 3.93 mmol, 1.00 equiv) and NaHCO₃ (0.400 g, 4.72 mmol, 1.20 equiv) inEt₂O (15.0 mL, 0.262 M) at 0° C. under N₂ was slowly added a solution ofacetyl chloride (0.370 g, 4.72 mmol, 1.20 equiv) in Et₂O (20.0 mL, 0.236M) via a syringe pump (at a rate of 10.0 mL/h). After the addition wascomplete, the reaction mixture was filtered through a short pad ofcelite and the celite was washed with EtOAc. The organic layers werecombined and concentrated in vacuo. The residue was purified bychromatography on silica gel, eluting with hexanes:EtOAc (4:1 to 1:1(v/v)), to afford the title compound as a yellow solid (0.570 g, 3.37mmol, 86% yield). R_(f)=0.10 (hexanes/EtOAc 4:1 (v/v)). NMRSpectroscopy: ¹H NMR (400 MHz, (CD₃)₂SO, δ): 10.66 (s, 1H), 7.66-7.60(m, 2H), 7.23-7.16 (m, 2H), 2.19 (s, 3H). ¹³C NMR (100 MHz, (CD₃)₂SO,δ): 169.7, 158.9 (d, J=240.2 Hz), 138.1 (d, J=2.6 Hz), 122.5, 115.0 5(d, J=22.3 Hz), 22.2. ¹⁹F NMR (376 MHz, (CD₃)₂SO, 25° C., δ): −120.2(s). Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₈H₉NO₂F([M+H]₊), 170.0617, found, 170.0620.

N-(4-Chlorophenyl)-N-hydroxyacetamide (1f)

To a stirred suspension of N-(4-chlorophenyl)hydroxylamine (S1f) (1.00g, 6.97 mmol, 1.00 equiv) and NaHCO₃ (0.700 g, 8.36 mmol, 1.20 equiv) inEt₂O (20.0 mL, 0.349 M) at 0° C. under N₂ was slowly added a solution ofacetyl chloride (0.660 g, 8.36 mmol, 1.20 equiv) in Et₂O (20.0 mL, 0.418M) via a syringe pump (at a rate of 10.0 mL/h). After the addition wascomplete, the reaction mixture was filtered through a short pad ofcelite and the celite was washed with EtOAc. The organic layers werecombined and concentrated in vacuo. Recrystallization from Et₂O/hexanesafforded the title compound as a yellow solid (1.15 g, 6.20 mmol, 89%yield). R_(f)=0.13 (hexanes/EtOAc 4:1 (v/v)). NMR Spectroscopy: ¹H NMR(400 MHz, (CD₃)₂SO, δ): 10.72 (s, 1H), 7.67 (d, J=8.9 Hz, 2H), 7.44-7.38(m, 2H), 2.21 (s, 3H). ₁₃C NMR (100 MHz, (CD₃)₂SO, δ): 170.1, 140.5,128.3, 128.1, 121.4, 22.5. Mass Spectrometry: HRMS (ESI-TOF) (m/z):calcd for C₈H₉NO₂Cl ([M+H]₊), 186.0322, found, 186.0321.

N-(4-Bromophenyl)-N-hydroxyacetamide (1g)

To a stirred suspension of N-(4-bromophenyl)hydroxylamine (S1g) (1.00 g,5.32 mmol, 1.00 equiv) and NaHCO₃ (0.540 g, 6.38 mmol, 1.20 equiv) inEt₂O (25.0 mL, 0.213 M) at 0° C. under N₂ was slowly added a solution ofacetyl chloride (0.500 g, 6.38 mmol, 1.20 equiv) in Et₂O (30.0 mL, 0.213M) via a syringe pump (at a rate of 10.0 mL/h). After the addition wascomplete, the reaction mixture was filtered through a short pad ofcelite and the celite was washed with EtOAc. The organic layers werecombined and concentrated in vacuo to afford the title compound as abrown solid (1.23 g, 5.34 mmol, quant yield). R_(f)=0.14 (hexanes/EtOAc4:1 (v/v)). NMR Spectroscopy: ¹H NMR (400 MHz, (CD₃)₂SO, δ): 10.72 (s,1H), 7.61 (d, J=9.0 Hz, 2H), 7.54 (d, J=9.0 Hz, 2H), 2.21 (s, 3H). ¹³HNMR (100 MHz, (CD₃)₂SO, δ): 170.2, 140.9, 131.2, 121.6, 116.2, 22.5.Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₈H₉NO₂Br ([M+H]₊),229.9817, found, 229.9818.

N-Hydroxy-N-(4-iodophenyl)acetamide (1h)

To a stirred suspension of N-(4-iodophenyl)hydroxylamine (S1h) (1.00 g,4.25 mmol, 1.00 equiv) and NaHCO₃ (0.430 g, 5.11 mmol, 1.20 equiv) inEt₂O (30.0 mL, 0.412 M) at 0° C. under N₂ was slowly added a solution ofacetyl chloride (0.400 g, 5.11 mmol, 1.20 equiv) in Et₂O (20.0 mL, 0.256M) via a syringe pump (at a rate of 10.0 mL/h). After the addition wascomplete, water was added. The aqueous layer was extracted with EtOAc (415 mL). The combined organic layers were dried (MgSO₄), filtered, andconcentrated in vacuo. Recrystallization from Et₂O/hexanes afforded thetitle compound as light brown solid (0.980 g, 3.54 mmol, 83% yield).R_(f)=0.18 (hexanes/EtOAc 4:1 (v/v)). NMR Spectroscopy: ¹H NMR (400 MHz,(CD₃)₂SO, δ): 10.69 (s, 1H), 7.72-7.67 (m, 2H), 7.48 (d, J=8.5 Hz, 2H),2.21 (s, 3H). ¹³C NMR (100 MHz, (CD₃)₂SO, δ): 170.1, 141.4, 137.0,121.8, 88.4, 22.6. Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd forC₈H₉NO₂I ([M+H]₊), 277.9678, found, 277.9684.

N-(3-Fluorophenyl)-N-hydroxyacetamide (1i)

To a stirred suspension of N-(3-fluorophenyl)hydroxylamine (S1i) (0.800g, 6.29 mmol, 1.00 equiv) and NaHCO₃ (0.634 g, 7.55 mmol, 1.20 equiv) inEt₂O (35.0 mL, 0.180 M) at 0° C. under N₂ was slowly added a solution ofacetyl chloride (0.593 g, 7.55 mmol, 1.20 equiv) in Et₂O (30.0 mL, 0.252M) via a syringe pump (at a rate of 10.0 mL/h). After the addition wascomplete, the reaction mixture was filtered through a short pad ofcelite and the celite was washed with EtOAc. The organic layers werecombined and concentrated in vacuo. The residue was purified bychromatography on silica gel, eluting with hexanes:EtOAc (4:1 to 1:1(v/v)), to afford the title compound as a yellow liquid (0.830 g, 4.91mmol, 78% yield). R_(f)=0.52 (hexanes/EtOAc 1:1 (v/v)). NMRSpectroscopy: ¹H NMR (500 MHz, (CD₃)₂SO, δ): 10.77 (s, 1H), 7.54-7.50(m, 2H), 7.50-7.37 (m, 1H), 7.00-7.6.94 (m, 1H), 2.23 (s, 3H). ¹³C NMR(125 MHz, (CD₃)₂SO, δ): 170.4, 161.80 (d, J=240.2 Hz), 143.1 (d, J=10.7Hz), 130.1 (d, J=9.2 Hz), 115.0, 110.7 (d, J=20.9 Hz), 106.3 (d, J=27.7Hz), 22.7. ¹⁹F NMR (376 MHz, (CD₃)₂SO, 25° C., δ): −114.5 (s). MassSpectrometry: HRMS (ESI-TOF) (m/z): calcd for C₈H₉NO₂F ([M+H]₊),170.0617, found, 170.0617.

N-(2-Bromophenyl)-N-hydroxyacetamide (1j)

To a stirred suspension of N-(2-bromophenyl)hydroxylamine (S1j) (0.820g, 4.36 mmol, 1.00 equiv) and NaHCO₃ (0.430 g, 5.23 mmol, 1.20 equiv) inEt₂O (20.0 mL, 0.218 M) at 0° C. under N₂ was slowly added a solution ofacetyl chloride (0.410 g, 5.23 mmol, 1.20 equiv) in Et₂O (25.0 mL, 0.209M) via a syringe pump (at a rate of 10.0 mL/h). After the addition wascomplete, the reaction mixture was filtered through a short pad ofcelite and the celite was washed with EtOAc. The organic layers werecombined and concentrated in vacuo. The residue was purified bychromatography on silica gel, eluting with hexanes:EtOAc (1:1 (v/v)), toafford the title compound as a brown solid (0.790 g, 3.43 mmol, 79%yield). R_(f)=0.21 (hexanes/EtOAc 1:1 (v/v)). NMR Spectroscopy: ¹H NMR(500 MHz, (CD₃)₂SO, δ): 10.65 (s, 1H), 7.71-7.70 (m, 1H), 7.45-7.44 (m,1H), 7.31-7.30 (m, 1H), 3.34 (s, 3H). ¹³C NMR (125 MHz, (CD₃)₂SO, δ):170.5, 141.0, 133.0, 129.9, 128.6, 122.1, 21.0. Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₈H₉NO₂Br ([M+H]₊), 229.9817, found,229.9820.

N-Hydroxy-N-(3-methoxy-5-(trifluoromethyl)phenyl)acetamide (1k)

To a stirred suspension of N-(3-methoxy-5-(trifluoromethyl)phenyl)hydroxylamine (S1k) (0.720 g, 3.48 mmol, 1.00 equiv) and NaHCO₃ (0.350g, 4.17 mmol, 1.20 equiv) in Et₂O (15.0 mL, 0.232 M) at 0° C. under N₂was slowly added a solution of acetyl chloride (0.330 g, 4.17 mmol, 1.20equiv) in Et₂O (20.0 mL, 0.209 M) via a syringe pump (at a rate of 10.0mL/h). After the addition was complete, the reaction mixture wasfiltered through a short pad of celite and the celite was washed withEtOAc. The organic layers were combined and concentrated in vacuo toafford the title compound as a yellow solid (0.870 g, 3.49 mmol, quantyield). R_(f)=0.18 (hexanes/EtOAc 4:1 (v/v)). NMR Spectroscopy: ¹H NMR(400 MHz, (CD₃)₂SO, δ): 10.87 (s, 1H), 7.64 (s, 1H), 7.53 (s, 1H), 7.01(s, 1H), 3.83 (s, 3H), 2.25 (s, 3H). ¹³C NMR (100 MHz, (CD₃)₂SO, δ):170.8, 159.8, 143.4, 130.2 (q, J=31.4 Hz), 123.9 (q, J=270.9 Hz), 108.6,107.9, 105.8, 55.7, 22.8. ¹⁹F NMR (376 MHz, (CD₃)₂SO, 25° C., δ): −63.3(s). Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₁₀H₁₁NO₃F₃([M+H]₊), 250.0691, found, 250.0696.

N-Hydroxy-N-(3-(trifluoromethyl)phenyl)acetamide (11)

To a stirred suspension of N-(3-(trifluoromethyl)phenyl)hydroxylamine(S1l) (0.720 g, 4.06 mmol, 1.00 equiv) and NaHCO₃ (0.410 g, 4.88 mmol,1.20 equiv) in Et₂O (20.0 mL, 0.203 M) at 0° C. under N₂ was slowlyadded a solution of acetyl chloride (0.380 g, 4.88 mmol, 1.20 equiv) inEt₂O (25.0 mL, 0.192 M) via a syringe pump (at a rate of 10.0 mL/h).After the addition was complete, the reaction mixture was filteredthrough a short pad of celite and the celite was washed with EtOAc. Theorganic layers were combined and concentrated in vacuo. The residue waspurified by chromatography on silica gel, eluting with hexanes:EtOAc(4:1 to 1:1 (v/v)), to afford the title compound as a yellow solid(0.760 g, 3.47 mmol, 85% yield). R_(f)=0.19 (hexanes/EtOAc 4:1 (v/v)).NMR Spectroscopy: ¹H NMR (500 MHz, (CD₃)₂SO, δ): 10.88 (s, 1H), 8.03 (s,1H), 7.94 (d, J=8.0 Hz, 1H), 7.61 (t, J=8.0 Hz, 1H), 7.48 (d, J=8.0 Hz,1H), 2.08 (s, 3H). ¹³C NMR (125 MHz, (CD₃)₂SO, δ): 170.7, 142.2, 129.8,129.1 (q, J=31.6 Hz), 126.2 (d, J=270.9 Hz), 122.9 (d, J=9.6 Hz), 120.6(d, J=29.7 Hz), 115.5, 22.6. ¹⁹F NMR (376 MHz, (CD₃)₂SO, 25° C., δ):−63.1 (s). Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₉H₉NO₂F₃([M+H]₊), 220.0585, found, 220.0589.

N-Hydroxy-N-(3-methoxyphenyl)acetamide (1m)

To a stirred suspension of N-(3-methoxyphenyl)hydroxylamine (S1m) (0.900g, 6.47 mmol, 1.00 equiv) and NaHCO₃ (0.650 g, 7.76 mmol, 1.20 equiv) inEt₂O (30.0 mL, 0.216 M) at 0° C. under N₂ was slowly added a solution ofacetyl chloride (0.610 g, 7.76 mmol, 1.20 equiv) in Et₂O (30.0 mL, 0.259M) via a syringe pump (at a rate of 10.0 mL/h). After the addition wascomplete, the reaction mixture was filtered through a short pad ofcelite and the celite was washed with EtOAc. The organic layers werecombined and concentrated in vacuo. The residue was purified bychromatography on silica gel, eluting with hexanes:EtOAc (5:1 to 4:1(v/v)), to afford the title compound as a brown liquid (0.810 g, 4.47mmol, 69% yield). R_(f)=0.26 (hexanes/EtOAc 5:1 (v/v)). ¹H NMR (500 MHz,(CD₃)₂SO, δ): 10.61 (s, 1H), 7.30-7.20 (m, 3H), 6.74-6.71 (m, 1H), 3.74(s, 3H), 2.19 (s, 3H). ¹³C NMR (125 MHz, (CD₃)₂SO, δ): 169.9, 159.2,142.8, 129.2, 112.3, 109.8, 106.0, 55.1, 22.6. Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₉H₁₂NO₃ ([M+H]₊), 182.0817, found, 182.0816.

Methyl 3-(N-hydroxyacetamido)benzoate (1n)

To a stirred suspension of methyl 3-(hydroxyamino)benzoate (S1n) (1.00g, 5.98 mmol, 1.00 equiv) and NaHCO₃ (0.600 g, 7.18 mmol, 1.20 equiv) inEt₂O (30.0 mL, 0.199 M) at 0° C. under N₂ was slowly added a solution ofacetyl chloride (0.560 g, 7.18 mmol, 1.20 equiv) in Et₂O (30.0 mL, 0.239M) via a syringe pump (at a rate of 10.0 mL/h). After the addition wascomplete, the reaction mixture was filtered through a short pad ofcelite and the celite was washed with EtOAc. The organic layers werecombined and concentrated in vacuo to afford the title compound as ayellow solid (1.25 g, 5.98 mmol, quant yield). R_(f)=0.10 (hexanes/EtOAc4:1 (v/v)). NMR Spectroscopy: ¹H NMR (400 MHz, (CD₃)₂SO, δ): 10.80 (s,1H), 8.26 (s, 1H), 7.95-7.90 (m, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.51 (t,J=7.9 Hz, 1H), 3.86 (s, 3H), 2.24 (s, 3H). ₁₃C NMR (100 MHz, (CD₃)₂SO,δ): 170.4, 166.0, 141.9, 129.8, 128.9, 124.9, 124.2, 120.1, 52.3, 22.5.Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₁₀H₁₂NO₄ ([M+H]₊),210.0766, found, 210.0764.

N-(2-Chloro-5-(trifluoromethyl)phenyl)-N-hydroxyacetamide (1o)

To a stirred suspension of N-(2-chloro-5-(trifluoromethyl)phenyl)hydroxylamine (S1o) (0.930 g, 4.43 mmol, 1.00 equiv) and NaHCO₃ (0.447g, 5.32 mmol, 1.20 equiv) in Et₂O (25.0 mL, 0.177 M) at 0° C. under N₂was slowly added a solution of acetyl chloride (0.417 g, 5.32 mmol, 1.20equiv) in Et₂O (20.0 mL, 0.266 M) via a syringe pump (at a rate of 10.0mL/h). After the addition was complete, the reaction mixture wasfiltered through a short pad of celite and the celite was washed withEtOAc. The organic layers were combined and concentrated in vacuo. Theresidue was purified by chromatography on silica gel, eluting withhexanes:EtOAc (4:1 to 2:1 (v/v)), to afford title compound as a yellowliquid (1.11 g, 4.38 mmol, quant yield). R_(f)=0.39 (hexanes/EtOAc 2:1(v/v)). ¹H NMR (500 MHz, (CD₃)₂SO, δ): 10.87 (s, 1H), 7.84-7.75 (m, 3H),2.19 (s, 3H). ¹³C NMR (125 MHz, (CD₃)₂SO, δ): 170.7, 140.3, 135.7,131.3, 128.6 (q, J=32.5 Hz), 126.3 (m), 125.9 (m), 123.3 (q, J=270.8Hz), 20.8. ¹⁹F NMR (376 MHz, (CD₃)₂SO, 25° C., δ): −63.2 (s). MassSpectrometry: HRMS (ESI-TOF) (m/z): calcd for C₉H₈NO₂ClF₃ ([M+H]₊),254.0196, found, 254.0194.

N-(3-Benzyl-8-chloro-4-oxo-3,4-dihydroquinazolin-7-yl)-N-hydroxyacetamide(1p)

To a stirred suspension of methyl 3-benzyl-8-chloro-7-(hydroxyamino)quinazolin-4(3H)-one (S1p) (0.700 g, 2.32 mmol, 1.00 equiv) and NaHCO₃(0.234 g, 2.78 mmol, 1.20 equiv) in Et₂O/THF 1:1 (v/v) (10 mL, 0.232 M)at 0° C. under N₂ was slowly added a solution of acetyl chloride (0.219g, 2.78 mmol, 1.20 equiv) in Et₂O (15.0 mL, 0.185M) via a syringe pump(at a rate of 10.0 mL/h). After the addition was complete, the reactionwas quenched with water, filtered and the solid was washed with Et₂O,dried at r.t. for 24 h to afford the title compound as a yellow solid(0.720 g, 2.09 mmol, 90% yield). R_(f)=0.14 (hexanes/EtOAc 4:1 (v/v)).NMR Spectroscopy: ¹H NMR (500 MHz, (CD₃)₂SO, δ): 10.83 (s, 1H), 8.65 (s,2H), 8.15 (s, 1H), 7.91 (s, 1H), 7.25-7.40 (m, 5H), 5.20 (s, 2H), 2.19(s, 3H). ¹³C NMR (125 MHz, (CD₃)₂SO, δ): 159.3, 150.0, 148.1, 138.1,137.7, 136.5, 128.7, 128.2, 127.8, 127.6, 126.7, 121.3, 49.1, 20.9. MassSpectrometry: HRMS (ESI-TOF) (m/z): calcd for C₁₇H₁₅N₃O₃Cl ([M+H]₊),344.0802, found, 344.0808.

Methyl 4-(N-hydroxyacetamido)benzoate (1q)

To a stirred suspension of methyl 4-(hydroxyamino)benzoate (S1q) (0.900g, 5.38 mmol, 1.00 equiv) and NaHCO₃ (0.540 g, 6.46 mmol, 1.20 equiv) inEt₂O (30.0 mL, 0.179 M) at 0° C. under N₂ was slowly added a solution ofacetyl chloride (0.510 g, 6.46 mmol, 1.20 equiv) in Et₂O (30.0 mL, 0.215M) via a syringe pump (at a rate of 10.0 mL/h). After the addition wascomplete, the reaction mixture was filtered through a short pad ofcelite and the celite was washed with EtOAc. The organic layers werecombined and concentrated in vacuo. The residue was purified bychromatography on silica gel, eluting with hexanes:EtOAc (4:1 to 1:1(v/v)), to afford the title compound as a light yellow solid (0.910 g,4.35 mmol, 81% yield). R_(f)=0.13 (hexanes/EtOAc4:1 (v/v)). NMRSpectroscopy: ¹H NMR (400 MHz, (CD₃)₂SO, δ): 10.83 (s, 1H), 7.96 (d,J=9.0 Hz, 2H), 7.83 (d, J=9.0 Hz, 2H), 3.83 (s, 3H), 2.26 (s, 3H). ¹³CNMR (100 MHz, (CD₃)₂SO, δ): 170.8, 165.7, 145.4, 129.8, 124.6, 118.4,52.0, 22.9. Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₁₀H₁₂NO₄([M+H]₊), 210.0766, found, 210.0766.

Methyl 4-(N-hydroxybenzamido)benzoate (1r)

To a stirred suspension of methyl 4-(hydroxyamino)benzoate (S1q) (1.00g, 5.98 mmol, 1.00 equiv) and NaHCO₃ (0.603 g, 7.18 mmol, 1.20 equiv) inEt₂O (30.0 mL, 0.199 M) at 0° C. under N₂ was slowly added a solution ofacetyl chloride (1.01 g, 7.18 mmol, 1.20 equiv) in Et₂O (30.0 mL, 0.239M) via a syringe pump (at a rate of 10.0 mL/h). After the addition wascomplete, the reaction mixture was filtered through a short pad ofcelite and the celite was washed with EtOAc. The organic layers werecombined and concentrated in vacuo. The residue was purified bychromatography on silica gel, eluting with hexanes:EtOAc (4:1 (v/v)), toafford the title compound as a light yellow solid (1.47 g, 5.42 mmol,91% yield). R_(f)=0.20 (hexanes/EtOAc 4:1 (v/v)). NMR Spectroscopy: ¹HNMR (500 MHz, (CD₃)₂SO, δ): 10.93 (s, 1H), 8.00 (d, J=8.8 Hz, 2H), 7.81(d, J=8.8 Hz, 2H), 7.69 (d, J=7.4 Hz, 2H), 7.52-7.44 (m, 3H), 3.85 (s,3H). ¹³C NMR (125 MHz, (CD₃)₂SO, δ): 168.6, 165.7, 145.9, 135.2, 130.6,129.8, 128.4, 127.9, 125.5, 120.0, 52.1. Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₁₅H₁₄NO₄ ([M+H]₊), 272.0923, found,272.0925.

Methyl 4-(hydroxy(methoxycarbonyl)amino)benzoate (1s)

To a stirred suspension of methyl 4-(hydroxyamino)benzoate (S1q) (0.800g, 4.84 mmol, 1.00 equiv) and NaHCO₃ (0.554 g, 6.55 mmol, 1.35 equiv) inEt₂O (15.0 mL, 0.323 M) at 0° C. under N₂ was slowly added a solution ofmethyl chloroformate (0.490 g, 5.50 mmol, 1.10 equiv) in Et₂O (15.0 mL,0.367 M) via a syringe pump (at a rate of 7.50 mL/h).

After the addition was complete, the reaction mixture was filteredthrough a short pad of celite and the celite was washed with EtOAc.

The organic layers were combined and concentrated in vacuo. The residuewas recrystallized from CH₂Cl₂/hexanes to afford the title compound as alight yellow solid (0.830 g, 3.69 mmol, 75% yield). R_(f)=0.34(hexanes/EtOAc 3:2 (v/v)). ¹H NMR (400 MHz, (CD₃)₂SO, δ): 10.63 (s, 1H),7.94 (d, J=9.0 Hz, 2H), 7.70 (d, J=9.0 Hz, 2H), 3.83 (s, 3H), 3.78 (s,3H). ¹³C NMR (125 MHz, (CD₃)₂SO, δ): 165.7, 154.3, 146.1, 129.8, 124.3,118.1, 53.2, 52.0. Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd forC₁₀H₁₂NO₅ ([M+H]₊), 226.0715, found, 226.0714.

Methyl 4-(1-hydroxy-3,3-dimethylureido)benzoate (1t)

To a stirred suspension of methyl 4-(hydroxyamino)benzoate (S1q) (1.00g, 5.98 mmol, 1.00 equiv) and NaHCO₃ (0.603 g, 7.18 mmol, 1.20 equiv) inEt₂O (30.0 mL, 0.199 M) at 0° C. under N₂ was slowly added a solution ofdimethylcarbamic chloride (0.772 g, 7.18 mmol, 1.2 equiv) in Et₂O (30.0mL, 0.239 M) via a syringe pump (at a rate of 10.0 mL/h). After theaddition was complete, the reaction was quenched by water and extractedwith EtOAc (20 mL×4). The combined organic layers were dried with MgSO₄,filtered, and concentrated in vacuo. The residue was recrystallized formEt₂O/hexanes to afford title compound as a yellow solid (0.780 g, 3.27mmol, 55% yield). R_(f)=0.25 (hexanes/EtOAc 4:1 (v/v)). NMRSpectroscopy: ¹H NMR (500 MHz, (CD₃)₂SO, δ): 10.14 (s, 1H), 7.87 (d,J=8.8 Hz, 2H), 7.23 (d, J=8.8 Hz, 2H), 3.81 (s, 3H), 2.95 (s, 6H). ¹³CNMR (125 MHz, (CD₃)₂SO, δ): 166.0, 159.0, 149.4, 129.6, 122.7, 117.0,51.8, 37.3. Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd forC₁₁H₁₅N₂O₄ ([M+H]₊), 239.1032, found, 239.1033.

N-Hydroxy-N-(p-tolyl)acetamide (1u)

To a stirred suspension of N-(p-tolyl)hydroxylamine (S1u) (0.200 g, 1.62mmol, 1.00 equiv) and NaHCO₃ (164 mg, 1.95 mmol, 1.20 equiv) in Et₂O(10.0 mL, 0.162 M) at 0° C. under N₂ was slowly added a solution ofacetyl chloride (153 mg, 1.95 mmol, 1.20 equiv) in Et₂O (5.00 mL, 0.390M) via a syringe pump (at a rate of 10.0 mL/h). After the addition wascomplete, the reaction mixture was filtered through a short pad ofcelite and concentrated in vacuo. The residue was purified bychromatography on silica gel, eluting with hexanes:EtOAc (4:1 to 2:1(v/v), to afford the title compound as a yellow solid (0.156 g, 0.944mmol, 58% yield). R_(f)=0.27 (hexanes/EtOAc 2:1 (v/v)). NMRSpectroscopy: ¹H NMR (400 MHz, (CD₃)₂SO, δ): 10.51 (s, 1H), 7.47 (d,J=8.2 Hz, 2H), 7.15 (d, J=8.2 Hz, 2H), 2.28 (s, 3H), 2.16 (s, 3H). ¹³CNMR (125 MHz, (CD₃)₂SO, δ): 169.5, 139.3, 133.8, 128.8, 120.3, 22.3,20.4. Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₉H₁₂NO₂([M+H]₊), 166.0868, found, 166.0867.

Methyl (R)-2-acetamido-3-(4-(N-hydroxyacetamido)phenyl) propanoate (1v)

To a stirred suspension of methyl(R)-2-acetamido-3-(4-(hydroxyamino)phenyl)propanoate (S1v) (0.910 g,3.61 mmol, 1.00 equiv) and NaHCO₃ (0.364 g, 4.33 mmol, 1.20 equiv) inEt₂O (20.0 mL, 0.185 M) at 0° C. under N₂ was slowly added a solution ofacetyl chloride (0.340 g, 4.33 mmol, 1.20 equiv) in Et₂O (20.0 mL, 0.217M) via a syringe pump (at a rate of 10.0 mL/h). After the addition wascomplete, the reaction mixture was slowly warmed up to rt. The reactionmixture was then quenched with water and the solid was collected byfiltration and dried under vacuum overnight at 40° C. The procedureafforded the title compound as a yellow solid (0.920 g, 3.13 mmol, 87%yield). NMR Spectroscopy: ¹H NMR (500 MHz, (CD₃)₂SO, δ): 10.57 (s, 1H),8.32 (d, J=7.2 Hz, 1H), 7.52 (d, J=7.7 Hz, 2H), 7.19 (d, J=7.7 Hz, 2H),4.43 (d, J=5.9 Hz, 1H), 3.60 (s, 3H), 2.98 (dd, J=5.9, 13.6 Hz, 1H),2.85 (dd, J=5.9, 13.6 Hz, 1H), 2.18 (s, 3H), 1.79 (s, 3H). ¹³C NMR (125MHz, (CD₃)₂SO, δ): 172.2, 169.7, 169.3, 140.2, 133.5, 129.0, 120.0,53.6, 51.8, 36.2, 22.4, 22.2. Mass Spectrometry: HRMS (ESI-TOF) (m/z):calcd for C₁₄H₁₉N₂O₅ ([M+H]₊), 295.1294, found, 295.1296.

Methyl hydroxy(quinolin-8-yl) carbamate (1w)

To a stirred suspension of N-(quinolin-8-yl)hydroxylamine (S1w) (0.50 g,3.12 mmol, 1.00 equiv) and NaHCO₃ (0.315 g, 3.75 mmol, 1.20 equiv) inEt₂O (15.0 mL, 0.208 M) at 0° C. under N₂ was slowly added a solution ofmethyl chloroformate (0.325 g, 3.75 mmol, 1.20 equiv) in Et₂O (16.0 mL,0.234 M) via a syringe pump (at a rate of 10.0 mL/h).

After the addition was complete, the reaction mixture was warmed up tort and stirred for another 4 h. The reaction mixture was quenched withwater and the solid was collected by filtration and dried under vacuumovernight. The procedure afforded the title compound as a dark brownsolid (0.550 g, 2.52 mmol, 81% yield). R_(f)=0.23 (hexanes/EtOAc 5:1(v/v)). NMR Spectroscopy: ¹H NMR (500 MHz, (CD₃)₂SO, δ): 10.19 (s, 1H),8.93 (dd, J=1.7, 4.2 Hz, 1H), 8.43 (dd, J=1.7, 8.3 Hz, 1H), 8.00 (dd,J=1.3, 8.3 Hz, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.64 (dd, J=7.6, 8.3 Hz,1H), 7.59 (dd, J=4.2, 8.3 Hz, 1H), 3.57 (s, 3H). ¹³C NMR (125 MHz,(CD₃)₂SO, δ): 157.2, 150.5, 143.0, 139.7, 136.4, 128.8, 128.66, 128.65,126.4, 121.9, 52.6. Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd forC₁₁H₁₁N₂O₃ ([M+H]₊), 219.0770, found, 219.0773.

N-hydroxy-N-(1-(phenylsulfonyl)-1H-indol-5-yl)acetamide (1x)

To a stirred suspension of N-(1-(phenylsulfonyl)-1H-indol-5-yl)hydroxylamine (S1x) (0.950 g, 3.31 mmol, 1.00 equiv) and NaHCO₃ (0.333g, 3.97 mmol, 1.20 equiv) in Et₂O (25.0 mL, 0.132M) at 0° C. under N₂was slowly added a solution of acetyl chloride (0.311 g, 3.97 mmol, 1.20equiv) in EtO₂O (20.0 mL, 0.199M) via a syringe pump (at a rate of 10.0mL/h). After the addition was complete, the reaction mixture wasfiltered through a short pad of celite and concentrated in vacuo. Theresidue was purified by chromatography on silica gel, eluting withhexanes:EtOAc (4:1 to 1:1 (v/v), to afford the title compound as a whitesolid (1.02 g, 3.09 mmol, 94% yield). R_(f)=0.19 (hexanes/EtOAc 2:1(v/v)). NMR Spectroscopy: ¹H NMR (500 MHz, (CD₃)₂SO, δ): 10.63 (s, 1H),7.97 (d, J=8.1 Hz, 2H), 7.92 (d, J=9.1 Hz, 1H), 7.82 (d, J=3.6 Hz, 1H),7.79 (s, 1H), 7.70-7.66 (m, 1H), 7.61-7.56 (m, 3H), 6.87 (d, J=3.6 Hz,1H), 2.18 (s, 3H). ¹³C NMR (125 MHz, (CD₃)₂SO, δ): 169.7, 137.8, 136.9,134.7, 131.3, 130.4, 129.8, 127.9, 126.6, 118.5, 113.7, 112.9, 109.9,22.2. Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₁₆H₁₅N₂O₄S([M+H]₊), 331.0753, found, 331.0759.

Example 1. General Method for O-trifluoromethylation/OCF₃-Migration

Herein is described the first synthesis, isolation, and characterizationof protected N-aryl-N-(trifluoromethoxy)amines and their application inthe synthesis of ortho-OCF₃ aniline derivatives (Scheme 1).

Standard Procedure for O-trifluoromethylation of ProtectedN-aryl-N-hydroxylamines

Under N₂ atmosphere, to a mixture of protected N-aryl-N-hydroxylamine(1.00 equiv) and Cs₂CO₃ (10 mol %) in CHCl₃ (0.100 M) was added Tognireagent II (1.20 equiv) and the reaction mixture was stirred at rt for14-23 h. The reaction mixture was then washed with sat. aq. NaHCO₃* andthe organic layer was collected, dried (MgSO₄), filtered, andconcentrated in vacuo. The residue was purified by chromatography onsilica gel. *The wash with sat. aq. NaHCO₃ was not necessary in case ofcompounds of low polarity, which could be easily separated from2-iodobenzoic acid by means column chromatography.

Standard Procedure for the Synthesis of Ortho-OCF₃ Aniline DerivativesVia OCF₃-Migration

A solution of protected N-aryl-N-(trifluoromethoxy)amine (0.400 mmol) inMeNO₂ (0.400 mL, 1.00 M) was heated at an appropriate temperature (e.g.,50° C., 80° C., 120° C. or 140° C.) under N₂ atmosphere for 11-48 h. Thereaction mixture was concentrated in vacuo. The residue was purified bychromatography on silica gel.

Example 2. Synthesis of N—OCF₃ Compounds

Although synthesis and applications of N—SCF₃ compounds areknown,^([15]) direct synthesis of the analogous N—OCF₃ compounds fromprotected N-aryl-N-hydroxylamines has not been reported.^([14]) It isknown that sodium 2,6,6-tetramethylpiperidin-1-oxide (TEMPONa) reactswith 1-trifluoromethyl-1,2-benziodoxol-3(1H)-one (Togni reagentII)^([16]) to form TEMPO-CF₃.^([17]) Based on this reactivity, Togni andco-workers developed O-trifluoromethylation of N,N-dialkylhydroxylaminesusing 3,3-Dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (Togni reagentI).^([14b]) Therefore, it was envisioned that protectedN-aryl-N-hydroxylamines could react with Togni reagents to provide thedesired products of O-trifluoromethylation. Indeed, treatment ofN-phenyl-N-hydroxamic acid (1a) with 1.2 equiv of Togni reagent II inthe presence of 10 mol % Cs₂CO₃ in CHCl₃ (0.1 M) at room temperaturefurnished the desired product 2a in 72% yield (Scheme 2). Addition of astoichiometric amount of radical trap,3,5-di-tert-butyl-4-hydroxytoluene (BHT), diminished the product yield.Moreover, this reaction is oxygen sensitive, so strictly degassedchloroform is required for high yield. These observations are consistentwith a radical reaction mechanism.^([14b,17])

Under the optimized reaction conditions, various protectedN-aryl-N-hydroxylamines (1a-1t, Scheme 2) were surveyed to determine thescope and limitations of this reaction. The reaction tolerated a widerange of functional groups including nitrile (2b), ketone (2c), amide(2d), halogens (2e-2j, 2o, 2p), CF₃ group (2k, 2l, 2o), ether (2k, 2m),ester (2n, 2q-2t), and heterocycle substituent (2p). Examination ofdifferent nitrogen protecting groups revealed that acetyl-, benzoyl-,and methoxycarbonyl-protected N-[(4-methoxycarbonyl) phenyl]hydroxylamines showed excellent and comparable reactivities (2q-2s),while dimethylcarbamoyl-protected N-[(4-methoxycarbonyl) phenyl]hydroxylamine was found to react sluggishly (2t). Substrates bearing adimethylcarbamoyl group (2d, 2t) afforded the corresponding products inlower yields. This is probably due to decomposition of thedimethylcarbamoyl group resulting from a hydrogen atom abstraction ofN□CH3 by a N-hydroxyl radical.^([18]) It is noteworthy that this classof the OCF3 compounds (2a-2t) shows the most shielded chemical shift(˜−65 ppm) in 19F-NMR compared to other OCF₃ containing compounds suchas TEMPO-CF3 (−55.7 ppm),^([19]) Ph-OCF3 (−58 ppm),^([20]) andn-C₁₀H₂₁—OCF₃ (−61.3 ppm).^([21])

Procedures for O-trifluoromethylation of ProtectedN-aryl-N-hydroxylamines N-Phenyl-N-(trifluoromethoxy)acetamide (2a)

Under N₂ atmosphere, to a mixture of N-hydroxy-N-phenylacetamide (1a)(400 mg, 2.65 mmol, 1.00 equiv) and Cs₂CO₃ (86.2 mg, 0.265 mmol, 10 mol%) in CHCl₃ (26.5 mL, 0.100 M) was added Togni reagent II (1.00 g, 3.18mmol, 1.20 equiv) and the reaction mixture was stirred at rt for 21 h.The reaction mixture concentrated in vacuo. The residue was purified bychromatography on silica gel, eluting with hexanes:EtOAc (19:1 to 9:1(v/v)), to afford the title compound as a slightly yellow oil (420 mg,1.92 mmol, 72% yield). R_(f)=0.63 (hexanes/EtOAc 9:1 (v/v)). NMRSpectroscopy: ¹H NMR (500 MHz, CDCl₃, 25° C., δ): 7.49-7.41 (m, 2H),7.41-7.31 (m, 3H), 2.22 (s, 3H). ¹³C NMR (125 MHz, CDCl₃, 25° C., δ):172.4, 140.4, 129.5, 129.4, 126.3, 122.9 (q, J=263.0 Hz), 22.0. ¹⁹F NMR(376 MHz, CDCl₃, (376 MHz, CDCl₃, 25° C., δ): −64.8 (s). 25° C., δ):−64.8 (s). Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₉H₉NO₂F₃([M+H]⁺), 220.0585, found, 220.0580.

N-(4-Cyanophenyl)-N-(trifluoromethoxy)acetamide (2b)

Under N₂ atmosphere, to a mixture ofN-(4-cyanophenyl)-N-hydroxyacetamide (1b) (200 mg, 1.14 mmol, 1.00equiv) and Cs₂CO₃ (37.0 mg, 0.114 mmol, 10 mol %) in CHCl₃ (11.4 mL,0.100 M) was added Togni reagent II (432 mg, 1.37 mmol, 1.20 equiv) andthe reaction mixture was stirred at rt for 23 h. The reaction mixturewas filtered and the filtrate was concentrated in vacuo. The residue waspurified by chromatography on silica gel, eluting with hexanes:CH₂Cl₂(1:2 to 0:1 (v/v)), to afford the title compound as an off-white solid(234 mg, 0.958 mmol, 84% yield). R_(f)=0.66 (CH₂Cl₂). NMR Spectroscopy:1H NMR (700 MHz, CDCl₃, 25° C., δ): 7.74-7.70 (m, 2H), 7.55-7.51 (m,2H), 2.38 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 172.4, 143.6,133.1, 123.8, 122.7 (q, J=265.2 Hz), 118.1, 111.6, 21.9. ¹⁹F NMR (376MHz, CDCl₃, 25° C., δ): −65.2 (s). Mass Spectrometry: HRMS (ESI-TOF)(m/z): calcd for C₁₀H₈N₂O₂F₃ ([M+H]⁺), 245.0538, found, 245.0541.

N-(4-Acetylphenyl)-N-(trifluoromethoxy)acetamide (2c)

Under N₂ atmosphere, to a mixture of methylN-(4-acetylphenyl)-N-hydroxyacetamide (1c) (309 mg, 1.60 mmol, 1.00equiv) and Cs₂CO₃ (52.1 mg, 0.160 mmol, 10 mol %) in CHCl₃ (16.0 mL,0.100 M) was added Togni reagent II (607 mg, 1.92 mmol, 1.20 equiv) andthe reaction mixture was stirred at rt for 16 h. The reaction mixturewas then washed with sat. aq. NaHCO₃ (30 mL) and the layers wereseparated. The organic layer was dried (MgSO₄), filtered, andconcentrated in vacuo. The residue was purified by chromatography onsilica gel, eluting with hexanes:EtOAc (9:1 to 7:3 (v/v)), to afford thetitle compound as a slightly yellow oil (314 mg, 1.20 mmol, 75% yield).R_(f)=0.62 (hexanes/EtOAc 4:1 (v/v)). NMR Spectroscopy: ¹H NMR (700 MHz,CDCl₃, 25° C., δ): 8.03-8.00 (m, 2H), 7.50-7.48 (m, 2H), 2.61 (s, 3H),2.33 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 196.9, 172.3, 143.9,136.5, 129.3, 124.0, 122.7 (q, J=264.2 Hz), 26.8, 21.9. ¹⁹F NMR (376MHz, CDCl₃, 25° C., δ): −65.00 (s). Mass Spectrometry: HRMS (ESI-TOF)(m/z): calcd for C₁₁H₁₁NO₃F₃ ([M+H]⁺), 262.0691, found, 262.0691.

N,N-Dimethyl-4-(N-(trifluoromethoxy)acetamido)benzamide (2d)

Under N₂ atmosphere, to a mixture of4-(N-hydroxyacetamido)-N,N-dimethylbenzamide (1d) (192 mg, 0.864 mmol,1.00 equiv) and Cs₂CO₃ (28.2 mg, 0.0864 mmol, 10 mol %) in CHCl₃ (8.64mL, 0.100 M) was added Togni reagent II (329 mg, 1.04 mmol, 1.20 equiv)and the reaction mixture was stirred at rt for 14 h. The reactionmixture was then washed with sat. aq. NaHCO₃ (30 mL) and the layers wereseparated. The organic layer was dried (MgSO₄), filtered andconcentrated in vacuo. The reaction mixture was purified by preparativeTLC using hexanes:EtOAc (7:3 (v/v)) for development (prep TLC wasdeveloped four times). The purification afforded the title compound as apink oil (98.4 mg, 0.339 mmol, 39% yield). R_(f)=0.30 (hexanes/EtOAc 2:3(v/v)). NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃, 25° C., δ): 7.49 (d,J=8.2 Hz, 2H), 7.42 (d, J=8.2 Hz, 2H), 3.12 (br. s, 3H), 2.99 (br. s,3H), 2.27 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 172.4, 170.5,141.1, 136.8, 128.2, 125.2, 122.8 (q, J=263.8 Hz), 39.7, 35.5, 21.9. ¹⁹FNMR (376 MHz, CDCl₃, 25° C., δ): −64.9 (s). Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for Cl₂H₁₄N₂O₃F₃ ([M+H]⁺), 291.0957, found,291.0958.

N-(4-Fluorophenyl)-N-(trifluoromethoxy)acetamide (2e)

Under N₂ atmosphere, to a mixture of N-(4-fluorophenyl)-hydroxyacetamide(1e) (200 mg, 1.18 mmol, 1.00 equiv) and CS₂CO₃ (38.5 mg, 0.118 mmol, 10mol %) in CHCl₃ (11.8 mL, 0.100 M) was added Togni reagent II (447 mg,1.42 mmol, 1.20 equiv) and the reaction mixture was stirred at rt for 14h. The reaction mixture was filtered and the filtrate was concentratedin vacuo. The residue was purified by chromatography on silica gel,eluting with hexanes:CH₂Cl₂ (1:1 to 0:1 (v/v)), to afford the titlecompound as a slightly yellow oil (206 mg, 0.868 mmol, 73% yield).R_(f)=0.42 (hexanes/CH₂Cl₂ 1:1 (v/v)). NMR Spectroscopy: ¹H NMR (700MHz, CDCl₃, 25° C., δ): 7.39-7.34 (m, 2H), 7.16-7.11 (m, 2H), 2.24 (s,3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 172.7, 162.7 (d, J=249.0 Hz),136.4 (d, J=2.6 Hz), 128.5, 122.9 (q, J=263.1 Hz), 116.6 (d, J=22.9 Hz),21.9. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −64.8 (s), −111.4 (s). MassSpectrometry: HRMS (ESI-TOF) (m/z): calcd for C₉H₈NO₂F₄ ([M+H]⁺),238.0491, found, 238.0493.

N-(4-Chlorophenyl)-N-(trifluoromethoxy)acetamide (2f)

Under N₂ atmosphere, to a mixture ofN-(4-chlorophenyl)-N-hydroxyacetamide (1f) (297 mg, 1.60 mmol, 1.00equiv) and Cs₂CO₃ (52.1 mg, 0.160 mmol, 10 mol %) in CHCl₃ (16.0 mL,0.100 M) was added Togni reagent II (607 mg, 1.92 mmol, 1.20 equiv) andthe reaction mixture was stirred at rt for 16 h. The reaction mixturewas filtered and the filtrate was concentrated in vacuo. The residue waspurified by chromatography on silica gel, eluting with hexanes:CH₂Cl₂(7:3 to 1:1 (v/v)), to afford the title compound a slightly yellow oil(284 mg, 1.12 mmol, 70% yield). R_(r)=0.59 (hexanes/CH₂Cl₂ 1:1 (v/v)).NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃, 25° C., δ): 7.42 (d, J=8.6 Hz,2H), 7.32 (d, J=8.6 Hz, 2H), 2.26 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25°C., δ): 172.6, 138.8, 135.0, 129.7, 127.1, 122.8 (q, J=263.7 Hz), 21.9.¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −64.9 (s). Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₉H₈NO₂F₃Cl ([M+H]⁺), 254.0196, found,254.0198.

N-(4-Bromophenyl)-N-(trifluoromethoxy)acetamide (2g)

Under N₂ atmosphere, to a mixture ofN-(4-bromophenyl)-N-hydroxyacetamide (1g) (368 mg, 1.60 mmol, 1.00equiv) and Cs₂CO₃ (52.1 mg, 0.160 mmol, 10 mol %) in CHCl₃ (16.0 mL,0.100 M) was added Togni reagent II (607 mg, 1.92 mmol, 1.20 equiv) andthe reaction mixture was stirred at rt for 18 h. The reaction mixturewas filtered and the filtrate was concentrated in vacuo. The residue waspurified by chromatography on silica gel, eluting with hexanes:CH₂Cl₂(1:1 to 1:3 (v/v)), to afford the title compound as a slightly yellowoil (384 mg, 1.29 mmol, 81% yield). R_(f)=0.47 (hexanes/CH₂Cl₂ 1:1(v/v)). NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃, 25° C., δ): 7.59-7.55(m, 2H), 7.23-7.28 (m, 2H), 2.26 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25°C., δ): 172.5, 139.3, 132.6, 127.2, 122.9, 122.8 (q, J=263.3 Hz), 21.8.¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −64.9 (s). Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₉H₈NO₂F₃Br ([M+H]⁺), 297.9690, found,297.9694.

N-(4-Iodophenyl)-N-(trifluoromethoxy)acetamide (2h)

Under N₂ atmosphere, to a mixture of N-hydroxy-N-(4-iodophenyl)acetamide(1h) (200 mg, 0.722 mmol, 1.00 equiv) and Cs₂CO₃ (23.5 mg, 0.0720 mmol,10 mol %) in CHCl₃ (7.20 mL, 0.100 M) was added Togni reagent II (274mg, 0.867 mmol, 1.20 equiv) and the reaction mixture was stirred at rtfor 18 h. The reaction mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by chromatography onsilica gel, eluting with hexanes:CH₂Cl₂ (1:1 (v/v)), to afford the titlecompound as a slightly yellow oil (205 mg, 0.594 mmol, 82% yield).R_(f)=0.48 (hexanes/CH₂Cl₂ 1:1 (v/v)). NMR Spectroscopy: ¹H NMR (700MHz, CDCl₃, 25° C., δ): 7.79-7.76 (m, 2H), 7.14-7.11 (m, 2H), 2.27 (s,3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 172.5, 140.1, 138.6, 127.2,122.8 (q, J=263.5 Hz), 94.4, 21.9. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ):−64.9 (s). Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₉H₈NO₂F₃I([M+H]⁺), 345.9552, found, 345.9549.

N-(3-Fluorophenyl)-N-(trifluoromethoxy)acetamide (2i)

Under N₂ atmosphere, to a mixture ofN-(3-fluorophenyl)-N-hydroxyacetamide (1i) (243 mg, 1.44 mmol, 1.00equiv) and Cs₂CO₃ (46.9 mg, 0.144 mmol, 10 mol %) in CHCl₃ (14.4 mL,0.100 M) was added Togni reagent II (546 mg, 1.73 mmol, 1.20 equiv) andthe reaction mixture was stirred at rt for 22 h. The reaction mixturewas concentrated in vacuo. The residue was purified by chromatography onsilica gel, eluting with hexanes:CH₂Cl₂ (1:1 to 1:3 (v/v)), to affordthe title compound as a slightly yellow oil (260 mg, 1.09 mmol, 76%yield). R_(f)=0.55 (hexanes/CH₂Cl₂ 1:1 (v/v)). NMR Spectroscopy: ¹H NMR(700 MHz, CDCl₃, 25° C., δ): 7.41 (td, J=8.2, 6.0 Hz, 1H), 7.19 (d,J=8.2 Hz, 1H), 7.13 (dt, J=9.4, 2.2 Hz, 1H), 7.08 (td, J=8.2, 1.7 Hz,1H), 2.28 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 172.5, 162.7 (d,J=246.8 Hz), 141.6 (d, J=9.8 Hz), 130.5 (d, J=8.8 Hz), 122.8 (q, J=263.4Hz), 121.0, 115.9 (d, J=20.9 Hz), 112.9 (d, J=24.0 Hz), 21.9. ¹⁹F NMR(376 MHz, CDCl₃, 25° C., δ): −65.0 (s), −111.2 (s). Mass Spectrometry:HRMS (EI-TOF) (m/z): calcd for C₉H₇NO₂F₄ ([M]⁺), 237.0413, found,237.0417.

N-(2-Bromophenyl)-N-(trifluoromethoxy)acetamide (2j)

Under N₂ atmosphere, to a mixture ofN-(2-bromophenyl)-N-hydroxyacetamide (1j) (368 mg, 1.60 mmol, 1.00equiv) and Cs₂CO₃ (52.1 mg, 0.160 mmol, 10 mol %) in CHCl₃ (16.0 mL,0.100 M) was added Togni reagent II (607 mg, 1.92 mmol, 1.20 equiv) andthe reaction mixture was stirred at rt for 23 h. The reaction mixturewas filtered and the filtrate was concentrated in vacuo. The residue waspurified by chromatography on silica gel, eluting with hexanes:CH₂Cl₂(1:1 to 0:1 (v/v)), to afford the title compound as a slightly yellowoil (367 mg, 1.23 mmol, 77% yield). R_(f)=0.55 (hexanes/CH₂Cl₂ 1:1(v/v)). NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃, 25° C., δ): 7.70 (d,J=7.7 Hz, 1H), 7.48 (d, J=7.7 Hz, 1H), 7.42 (t, J=7.5 Hz, 1H), 7.36-7.31(m, 1H), 2.23 (br. s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 172.6,139.6, 134.2, 132.0, 131.3, 128.7, 123.6, 123.0 (q, J=263.0 Hz), 21.6.¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −64.6 (s). Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₉H₃NO₂F₃Br ([M+H]⁺), 297.9690, found,297.9688.

N-(3-Methoxy-5-(trifluoromethyl)phenyl)-N-(trifluoromethoxy) acetamide(2k)

Under N₂ atmosphere, to a mixture ofN-hydroxy-N-(3-methoxy-5-(trifluoromethyl)phenyl)acetamide (1k) (399 mg,1.60 mmol, 1.00 equiv) and Cs₂CO₃ (52.1 mg, 0.160 mmol, 10 mol %) inCHCl₃ (16.0 mL, 0.100 M) was added Togni reagent II (607 mg, 1.92 mmol,1.20 equiv) and the reaction mixture was stirred at rt for 18 h. Thereaction mixture was filtered and the filtrate was concentrated invacuo. The residue was purified by chromatography on silica gel, elutingwith hexanes:CH₂Cl₂ (1:3 to 3:1 (v/v)), to afford the title compound asa slightly yellow oil (417 mg, 1.31 mmol, 82% yield). R_(f)=0.33(hexanes/CH₂Cl₂ 3:2 (v/v)). NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃,25° C., δ): 7.24 (br. s, 1H), 7.12 (br. s, 1H), 7.09 (br. s, 1H), 3.87(s, 3H), 2.32 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 172.7,160.4, 141.8, 132.7 (q, J=33.0 Hz), 123.4 (q, J=271.1 Hz), 122.8 (q,J=264.0 Hz), 114.5, 113.9, 111.2, 56.0, 21.8. ¹⁹F NMR (376 MHz, CDCl₃,25° C., δ): −63.4 (s), −65.0 (s). Mass Spectrometry: HRMS (ESI-TOF)(m/z): calcd for C₁₁H₁₀NO₃F₆ ([M+H]⁺), 318.0565, found, 318.0569.

N-(Trifluoromethoxy)-N-(3-(trifluoromethyl)phenyl)acetamide (21)

Under N₂ atmosphere, to a mixture ofN-hydroxy-N-(3-(trifluoromethyl)phenyl)acetamide (11) (351 mg, 1.60mmol, 1.00 equiv) and Cs₂CO₃ (52.1 mg, 0.160 mmol, 10 mol %) in CHCl₃(16.0 mL, 0.100 M) was added Togni reagent II (607 mg, 1.92 mmol, 1.20equiv) and the reaction mixture was stirred at rt for 15 h. The reactionmixture was filtered and the filtrate was concentrated in vacuo. Theresidue was purified by chromatography on silica gel, eluting withhexanes:CH₂Cl₂ (1:1 to 0:1 (v/v)), to afford the title compound as aslightly yellow oil (378 mg, 1.32 mmol, 82% yield). R_(f)=0.50(hexanes/CH₂Cl₂ 1:1 (v/v)). NMR Spectroscopy: ¹H NMR (500 MHz, CDCl₃,25° C., δ): 7.66 (s, 1H), 7.64-7.60 (m, 1H), 7.60-7.56 (m, 2H), 2.33 (s,3H). ¹³C NMR (125 MHz, CDCl₃, 25° C., δ): 172.8, 140.8, 132.0 (q, J=33.0Hz), 129.9, 128.3, 125.4 (q, J=3.1 Hz), 123.5 (q, J=271.1 Hz), 122.8 (q,J=264.0 Hz), 121.7, 21.8. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −63.3(s), −65.0 (s). Mass Spectrometry: HRMS (EI-TOF) (m/z): calcd forC₁₀H₇NO₂F₆ ([M]⁺), 287.0381, found, 287.0389.

N-(3-Methoxyphenyl)-N-(trifluoromethoxy)acetamide (2m)

Under N₂ atmosphere, to a mixture ofN-hydroxy-N-(3-methoxyphenyl)acetamide (1m) (290 mg, 1.60 mmol, 1.00equiv) and Cs₂CO₃ (52.1 mg, 0.160 mmol, 10 mol %) in CHCl₃ (16.0 mL,0.100 M) was added Togni reagent II (607 mg, 1.92 mmol, 1.20 equiv) andthe reaction mixture was stirred at rt for 19 h. The reaction mixturewas concentrated in vacuo. The residue was purified by chromatography onsilica gel, eluting with hexanes:CH₂Cl₂ (1:1 to 3:7 (v/v)), to affordthe title compound as a yellow oil (303 mg, 1.21 mmol, 76% yield).R_(f)=0.34 (hexanes/CH₂Cl₂ 1:1 (v/v)). NMR Spectroscopy: ¹H NMR (700MHz, CDCl₃, 25° C., δ): 7.35 (t, J=8.2 Hz, 1H), 6.99-6.96 (m, 1H), 6.94(dd, J=8.4, 1.9 Hz, 1H), 6.93-6.90 (m, 1H), 3.83 (s, 3H), 2.21 (s, 3H).¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 172.4, 160.4, 141.4, 130.2, 122.9(q, J=262.7 Hz), 118.5, 115.2, 112.0, 55.6, 22.0. ¹⁹F NMR (376 MHz,CDCl₃, 25° C., δ): −64.8 (s). Mass Spectrometry: HRMS (ESI-TOF) (m/z):calcd for C₁₀H₁₁NO₃F₃ ([M+H]⁺), 250.0691, found, 250.0687.

Methyl 3-(N-(trifluoromethoxy)acetamido)benzoate (2n)

Under N₂ atmosphere, to a mixture of methyl3-(N-hydroxyacetamido)benzoate (in) (335 mg, 1.60 mmol, 1.00 equiv) andCs₂CO₃ (52.1 mg, 0.160 mmol, 10 mol %) in CHCl₃ (16.0 mL, 0.100 M) wasadded Togni reagent II (607 mg, 1.92 mmol, 1.20 equiv) and the reactionmixture was stirred at rt for 15 h. The reaction mixture was filteredand the filtrate was concentrated in vacuo. The residue was purified bychromatography on silica gel, eluting with hexanes:CH₂Cl₂ (1:3 to 0:1(v/v)), to afford the title compound as a slightly yellow oil (298 mg,1.08 mmol, 67% yield). R_(f)=0.50 (CH₂Cl₂). NMR Spectroscopy: ¹H NMR(500 MHz, CDCl₃, 25° C., δ): 8.07-8.04 (m, 2H), 7.59-7.56 (m, 1H),7.55-7.50 (m, 1H), 3.94 (s, 3H), 2.29 (s, 3H). ¹³C NMR (125 MHz, CDCl₃,25° C., δ): 172.7, 166.0, 140.6, 131.7, 130.0, 129.9, 129.5, 126.5,122.8 (q, J=263.7 Hz), 52.6, 21.8. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ):−64.9 (s). Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd forC₁₁H₁₁NO₄F₃ ([M+H]⁺), 278.0640, found, 278.0640.

Methyl 2-methyl-3-(N-(trifluoromethoxy)acetamido)benzoate (2o)

Under N₂ atmosphere, to a mixture ofN-(2-chloro-5-(trifluoromethyl)phenyl)-N-hydroxyacetamide (1o) (406 mg,1.60 mmol, 1.00 equiv) and Cs₂CO₃ (52.1 mg, 0.160 mmol, 10 mol %) inCHCl₃ (16.0 mL, 0.100 M) was added Togni reagent II (607 mg, 1.92 mmol,1.20 equiv) and the reaction mixture was stirred at rt for 14 h. Thereaction mixture was filtered and the filtrate was concentrated invacuo. The residue was purified by chromatography on silica gel, elutingwith hexanes:CH₂Cl₂ (1:1 to 1:3 (v/v)), to afford the title compound asa slightly yellow oil (388 mg, 1.21 mmol, 75% yield). R_(f)=0.64(hexanes/CH₂Cl₂ 1:1 (v/v)). NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃,25° C., δ): 7.73 (s, 1H), 7.69-7.64 (m, 2H), 2.35 (br. s, 3H). ¹³C NMR(175 MHz, CDCl₃, 25° C., δ): 173.3, 138.8, 137.5, 131.6, 130.7 (q,J=33.7 Hz), 128.4 (d, J=1.8 Hz), 127.9, 123.0 (q, J=271.1 Hz), 123.0 (q,J=263.8 Hz), 21.3. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −63.3 (s), −65.0(s). Mass Spectrometry: HRMS (EI-TOF) (m/z): calcd for C₁₀H₆NO₂F₆Cl([M]⁺), 320.9991, found, 320.9998.

N-(3-Benzyl-8-chloro-4-oxo-3,4-dihydroquinazolin-7-yl)-N-(trifluoromethoxy)acetamide(2p)

Under N₂ atmosphere, to a mixture ofN-(3-benzyl-8-chloro-4-oxo-3,4-dihydroquinazolin-7-yl)-N-hydroxyacetamide(1p) (402 mg, 1.16 mmol, 1.00 equiv) and Cs₂CO₃ (37.8 mg, 0.116 mmol, 10mol %) in CHCl₃ (11.6 mL, 0.100 M) was added Togni reagent II (439 g,1.39 mmol, 1.20 equiv) and the reaction mixture was stirred at rt for 21h. The reaction mixture was concentrated in vacuo. The residue waspurified by chromatography on silica gel, eluting with hexanes:EtOAc(7:3 to 3:2 (v/v)), to afford the title compound as a white solid (351mg, 0.852 mmol, 73% yield). R_(f)=0.52 (hexanes/EtOAc 3:2 (v/v)). NMRSpectroscopy: ¹H NMR (700 MHz, CDCl₃, 25° C., δ): 8.41 (s, 1H), 8.15 (s,1H), 7.85 (s, 1H), 7.40-7.31 (m, 5H), 5.19 (s, 2H), 2.33 (br. s, 3H).¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 173.2, 159.8, 149.9, 148.9, 139.3,136.9, 135.2, 129.8, 129.7, 129.3, 128.8, 128.2, 123.0 (q, J=263.5 Hz),121.6, 50.0, 21.3. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −64.7 (s). MassSpectrometry: HRMS (ESI-TOF) (m/z): calcd for C₁₈H₁₄N₃O₃ClF₃ ([M+H]⁺),412.0676, found, 412.0673.

Methyl 4-(N-(trifluoromethoxy)acetamido)benzoate (2q)

Under N₂ atmosphere, to a mixture of methyl4-(N-hydroxyacetamido)benzoate (1q) (335 mg, 1.60 mmol, 1.00 equiv) andCs₂CO₃ (52.1 mg, 0.160 mmol, 10 mol %) in CHCl₃ (16.0 mL, 0.100 M) wasadded Togni reagent II (607 mg, 1.92 mmol, 1.20 equiv) and the reactionmixture was stirred at rt for 16 h. The reaction mixture was filteredand the filtrate was concentrated in vacuo. The residue was purified bychromatography on silica gel, eluting with hexanes:CH₂Cl₂ (7:3 to 0:1(v/v)), to afford the title compound as a slightly yellow oil (428 mg,1.54 mmol, 97% yield). R_(f)=0.44 (CH₂Cl₂). NMR Spectroscopy: ¹H NMR(700 MHz, CDCl₃, 25° C., δ): 8.13-8.09 (m, 2H), 7.49-7.45 (m, 2H), 3.93(s, 3H), 2.33 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 172.3,166.2, 143.9, 130.6, 129.9, 124.0, 122.8 (q, J=264.1 Hz), 52.5, 21.9.¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −65.00 (s). Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₁₁H₁₁NO₄F₃ ([M+H]⁺), 278.0640, found,278.0637.

Methyl 4-(N-(trifluoromethoxy)benzamido)benzoate (2r)

Under N₂ atmosphere, to a mixture of methyl4-(N-hydroxybenzamido)benzoate (1r) (434 mg, 1.60 mmol, 1.00 equiv) andCs₂CO₃ (52.1 mg, 0.160 mmol, 10 mol %) in CHCl₃ (16.0 mL, 0.100 M) wasadded Togni reagent II (607 mg, 1.92 mmol, 1.20 equiv) and the reactionmixture was stirred at rt for 19 h. The reaction mixture was filteredand the filtrate was concentrated in vacuo. The residue was purified bychromatography on silica gel, eluting with hexanes:CH₂Cl₂ (1:1 to 0:1(v/v)), to afford the title compound as a slightly yellow oil (521 mg,1.54 mmol, 96% yield). R_(f)=0.67 (CH₂Cl₂). NMR Spectroscopy: ¹H NMR(700 MHz, CDCl₃, 25° C., δ): 8.03 (d, J=8.6 Hz, 2H), 7.65-7.61 (m, 2H),7.47-7.41 (m, 3H), 7.32 (t, J=7.7 Hz, 2H), 3.90 (s, 3H). ¹³C NMR (175MHz, CDCl₃, 25° C., δ): 170.7, 165.9, 145.2, 132.5, 132.1, 131.1, 131.0,129.2, 128.6, 127.2, 122.8 (q, J=265.8 Hz), 52.6. ¹⁹F NMR (376 MHz,CDCl₃, 25° C., δ): −64.4 (s). Mass Spectrometry: HRMS (ESI-TOF) (m/z):calcd for C₁₆H₁₃NO₄F₃ ([M+H]⁺), 340.0797, found, 340.0801.

Methyl 4-((methoxycarbonyl) (trifluoromethoxy)amino)benzoate (2s)

Under N₂ atmosphere, to a mixture of methyl4-(hydroxy(methoxycarbonyl)amino)benzoate (is) (360 mg, 1.60 mmol, 1.00equiv) and Cs₂CO₃ (52.1 mg, 0.160 mmol, 10 mol %) in CHCl₃ (16.0 mL,0.100 M) was added Togni reagent II (607 mg, 1.92 mmol, 1.20 equiv) andthe reaction mixture was stirred at rt for 20 h. The reaction mixturewas then washed with sat. aq. NaHCO₃ (30 mL) and the layers wereseparated. The organic layer was dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by chromatography onsilica gel, eluting with hexanes:CH₂Cl₂ (1:3 to 0:1 (v/v)), to affordthe title compound as a colorless oil (427 mg, 1.45 mmol, 91% yield).R_(f)=0.70 (CH₂Cl₂). NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃, 25° C.,δ): 8.09 (d, J=8.6 Hz, 2H), 7.48 (d, J=8.6 Hz, 2H), 3.93 (s, 3H), 3.89(s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 166.2, 155.4, 144.7,130.6, 129.6, 123.3, 122.8 (q, J=263.1 Hz), 54.9, 52.5. ¹⁹F NMR (376MHz, CDCl₃, 25° C., δ): −66.1 (s). Mass Spectrometry: HRMS (ESI-TOF)(m/z): calcd for C₁₁H₁₁NO₅F₃ ([M+H]⁺), 294.0589, found, 294.0589.

Methyl 4-(3,3-dimethyl-1-(trifluoromethoxy) ureido)benzoate (2t)

Under N₂ atmosphere, to a mixture of methyl4-(1-hydroxy-3,3-dimethylureido)benzoate (it) (185 mg, 0.777 mmol, 1.00equiv) and Cs₂CO₃ (25.3 mg, 0.0777 mmol, 10 mol %) in CHCl₃ (7.77 mL,0.100 M) was added Togni reagent II (295 mg, 0.932 mmol, 1.20 equiv) andthe reaction mixture was stirred at rt for 14 h. The reaction mixturewas then washed with sat. aq. NaHCO₃ (30 mL) and the layers wereseparated. The organic layer was dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by chromatography onsilica gel, eluting with CH₂Cl₂, to afford the title compound as acolorless oil (94.8 mg, 0.310 mmol, 40% yield). R_(f)=0.28 (CH₂Cl₂). NMRSpectroscopy: ¹H NMR (700 MHz, CDCl₃, 25° C., δ): 8.08 (d, J=8.6 Hz,2H), 7.28 (d, J=8.60 Hz, 2H), 3.92 (s, 3H), 2.97 (s, 6H). ¹³C NMR (175MHz, CDCl₃, 25° C., δ): 166.1, 158.0, 146.5, 131.4, 129.5, 122.9 (q,J=259.8 Hz), 122.2, 52.5, 37.3. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ):−65.1 (s). Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd forC₁₂H₁₄N₂O₄F₃ ([M+H]⁺), 307.0906, found, 307.0910.

Example 3. OCF₃ Migration

With the protected N-aryl-N-(trifluoromethoxy)amines (2a-2t) in hand,attention was directed to examining the OCF₃-migration reaction.Systematic variation of different reaction parameters, includingsolvent, concentration, and temperature, identified optimal reactionconditions. A significant degree of structural and electronic variationon the aryl ring was tolerated (Scheme 3). Products derived fromelectron-rich (3m) and electron-poor (3b-3l, 3n-3t) aniline derivativeswere formed in high yields, though electron-poor aniline derivativeswith exception of 3p required higher reaction temperatures for fullconversion. Notably, halogen functionalities, in particular Br and I,remained intact after reaction (3e-3j, 3o, 3p). These groups provideeasy handles for further synthetic elaborations. Other functional groupsincluding ester (3n, 3q-3t), nitrile (3b), ketone (3c), ether (3k, 3m),heterocycle (3p) and multiple substitution on arene (3k, 3o, 3p) werewell tolerated under the reaction conditions. In general, this reactionshowed high levels of ortho-selectivity (3a, 3i-3o); although, in thepresence of two non-identical ortho positions, low levels ofregiocontrol were obtained (3i, 3k-3n).

N-(2-(Trifluoromethoxy)phenyl)acetamide (3a) andN-(4-(trifluoromethoxy)phenyl)acetamide (3a-II)

A solution of N-phenyl-N-(trifluoromethoxy)acetamide (2a) (128 mg, 100μL, 0.584 mmol) in MeNO₂ (0.584 mL, 1.00 M) was heated at 80° C. underN₂ atmosphere for 19 h. The reaction mixture was concentrated in vacuo.The residue was purified by chromatography on silica gel, eluting withhexanes:EtOAc (9:1 to 1:1 (v/v)), to afford 3a (105 mg, 0.479 mmol, 82%yield) and 3a-II (11.2 mg, 0.0511 mmol, 9% yield). Data for 3a: whitesolid; R_(f)=0.36 (hexanes/EtOAc 4:1 (v/v)). NMR Spectroscopy: ¹H NMR(700 MHz, CDCl₃, 25° C., δ): 8.39 (d, J=8.2 Hz, 1H), 7.39 (br. s, 1H),7.28 (t, J=7.7 Hz, 1H), 7.25-7.24 (m, 1H), 7.12-7.08 (m, 1H), 2.23 (s,3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 168.4, 138.1, 130.7, 127.7,124.3, 122.1, 120.7 (q, J=257.7 Hz), 120.4, 25.0. ¹⁹F NMR (376 MHz,CDCl₃, 25° C., δ): −58.4 (s). Mass Spectrometry: HRMS (ESI-TOF) (m/z):calcd for C₉H₉NO₂F₃ ([M+H]⁺), 220.0585, found, 220.0583.

Data for 3a-II: white solid; R_(f)=0.33 (hexanes/EtOAc 3:2 (v/v)). NMRSpectroscopy: ¹H NMR (500 MHz, CDCl₃, 25° C., δ): 7.53 (d, J=8.9 Hz,2H), 7.18 (app d, J=8.9 Hz, 3H), 2.19 (s, 3H). ¹³C NMR (175 MHz, CDCl₃,25° C., δ): 168.4, 145.4, 136.6, 121.9, 121.1, 120.6 (q, J=255.5 Hz),24.7. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −58.8 (s). Mass Spectrometry:HRMS (ESI-TOF) (m/z): calcd for C₉H₉NO₂F₃ ([M+H]⁺), 220.0585, found,220.0583.

N-(4-Cyano-2-(trifluoromethoxy)phenyl)acetamide (3b)

A solution of N-(4-cyanophenyl)-N-(trifluoromethoxy)acetamide (2b) (97.7mg, 0.400 mmol) in MeNO₂ (0.400 mL, 1.00 M) was heated at 120° C. underN₂ atmosphere for 48 h. The reaction mixture was purified by preparativeTLC using hexanes:EtOAc (7:3 (v/v)) for development. The purificationafforded the title compound as a white crystalline solid (61.4 mg, 0.251mmol, 63% yield). 20.0 mg (20%) of the starting material was recovered.Data for 3b: R_(f)=0.64 (hexanes/EtOAc 3:2 (v/v)). NMR Spectroscopy: ¹HNMR (700 MHz, CDCl₃, 25° C., δ): 8.66 (d, J=8.6 Hz, 1H), 7.61 (br. s,1H), 7.58 (d, J=8.6 Hz, 1H), 7.54 (s, 1H), 2.28 (s, 3H). ¹³C NMR (175MHz, CDCl₃, 25° C., δ): 168.6, 137.1, 135.0, 132.0, 123.7, 121.8, 120.5(q, J=260.2 Hz), 117.6, 107.2, 25.2. ¹⁹F NMR (376 MHz, CDCl₃, 25° C.,δ): −58.4 (s). Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd forC₁₀H₈N₂O₂F₃ ([M+H]⁺), 245.0538, found, 245.0539.

N-(4-Acetyl-2-(trifluoromethoxy)phenyl)acetamide (3c)

A solution of N-(4-acetylphenyl)-N-(trifluoromethoxy)acetamide (2c) (104mg, 0.400 mmol) in MeNO₂ (0.400 mL, 1.00 M) was heated at 120° C. underN₂ atmosphere for 20 h. The reaction mixture was concentrated in vacuo.The residue was purified by chromatography on silica gel, eluting withhexanes:EtOAc (9:1 to 3:2 (v/v)), to afford the title compound as awhite solid (93.6 mg, 0.358 mmol, 90% yield). R_(f)=0.46 (hexanes/EtOAc3:2 (v/v)). NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃, 25° C., δ): 8.59(d, J=8.6 Hz, 1H), 7.89-7.86 (m, 2H), 7.58 (br. s, 1H), 2.59 (s, 3H),2.27 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 195.7, 168.6, 137.6,134.8, 132.9, 128.4, 120.8, 120.6 (q, J=259.1 Hz), 119.8, 26.5, 25.1.¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −58.0 (s). Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₁₁H₁₁NO₃F₃ ([M+H]⁺), 262.0691, found,262.0692.

4-Acetamido-N,N-dimethyl-3-(trifluoromethoxy)benzamide (3d)

A solution of N,N-dimethyl-4-(N-(trifluoromethoxy)acetamido) benzamide(2d) (42.1 mg, 0.145 mmol) in MeNO₂ (0.145 mL, 1.00 M) was heated at120° C. under N₂ atmosphere for 16 h. The reaction mixture was purifiedby preparative TLC using hexanes:EtOAc (3:7 (v/v)) for development (prepTLC was developed three times). The purification afforded the titlecompound as a white solid (30.0 mg, 0.103 mmol, 71% yield). R_(f)=0.36(hexanes/EtOAc 3:7 (v/v)). NMR Spectroscopy: 1H NMR (700 MHz, CDCl₃, 25°C., δ): 8.38 (d, J=8.2 Hz, 1H), 7.72 (br. s, 1H), 7.35-7.30 (m, 2H),3.08 (br. s, 3H), 2.99 (br. s, 3H), 2.23 (s, 3H). ¹³C NMR (175 MHz,CDCl₃, 25° C., δ): 169.7, 168.7, 137.8, 132.0, 131.8, 126.5, 121.8,120.6 (q, J=258.5 Hz), 119.9, 39.7, 35.7, 24.8. ¹⁹F NMR (376 MHz, CDCl₃,25° C., δ): −58.1 (s). Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcdfor C₁₂H₁₄N₂O₃F₃ ([M+H]⁺), 291.0957, found, 291.0953.

N-(4-Fluoro-2-(trifluoromethoxy)phenyl)acetamide (3e)

A solution of N-(4-fluorophenyl)-N-(trifluoromethoxy)acetamide (2e)(94.9 mg, 0.400 mmol) in MeNO₂ (0.400 mL, 1.00 M) was heated at 80° C.under N₂ atmosphere for 13 h. The reaction mixture was concentrated invacuo. The residue was purified by chromatography on silica gel, elutingwith hexanes:EtOAc (4:1 to 3:2 (v/v)), to afford the title compound as abeige solid (83.7 mg, 0.353 mmol, 88% yield). R_(f)=0.33 (hexanes/EtOAc4:1 (v/v)). NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃, 25° C., δ):8.38-8.30 (m, 1H), 7.30-7.26 (m, 1H), 7.08-6.98 (m, 2H), 2.22 (s, 3H).¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 168.3, 158.4 (d, J=245.1 Hz), 138.4(d, J=10.0 Hz), 126.9 (d, J=3.5 Hz), 123.4 (d, J=8.5 Hz), 120.5 (q,J=259.0 Hz), 114.3 (d, J=21.5 Hz), 108.4 (d, J=26.4 Hz), 24.8. ¹⁹F NMR(376 MHz, CDCl₃, 25° C., δ): −58.4 (s), −115.8 (m). Mass Spectrometry:HRMS (ESI-TOF) (m/z): calcd for C₉H₈NO₂F₄ ([M+H]⁺), 238.0491, found,238.0488.

N-(4-Chloro-2-(trifluoromethoxy)phenyl)acetamide (3f)

A solution of N-(4-chlorophenyl)-N-(trifluoromethoxy)acetamide (2f) (101mg, 0.400 mmol) in MeNO₂ (0.400 mL, 1.00 M) was heated at 80° C. underN₂ atmosphere for 15 h. The reaction mixture was concentrated in vacuo.The residue was purified by chromatography on silica gel, eluting withhexanes:EtOAc (4:1 to 3:2 (v/v)), to afford the title compound as abeige solid (86.2 mg, 0.340 mmol, 85% yield). R_(f)=0.41 (hexanes/EtOAc4:1 (v/v)). NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃, 25° C., δ): 8.38(d, J=9.0 Hz, 1H), 7.34 (br. s, 1H), 7.28-7.27 (m, 1H), 7.27-7.26 (m,1H), 2.23 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 168.3, 138.1,129.4, 128.9, 127.8, 122.8, 120.8, 120.6 (q, J=259.1 Hz), 24.9. ¹⁹F NMR(376 MHz, CDCl₃, 25° C., δ): −58.2 (s). Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₉H₈NO₂F₃Cl ([M+H]⁺), 254.0196, found,254.0193.

N-(4-Bromo-2-(trifluoromethoxy)phenyl)acetamide (3g)

A solution of N-(4-bromophenyl)-N-(trifluoromethoxy)acetamide (2g) (119mg, 0.400 mmol) in MeNO₂ (0.400 mL, 1.00 M) was heated at 80° C. underN₂ atmosphere for 14 h. The reaction mixture was concentrated in vacuo.The residue was purified by chromatography on silica gel, eluting withhexanes:EtOAc (17:1 to 7:3 (v/v)), to afford the title compound as abeige solid (107 mg, 0.359 mmol, 90% yield). R_(f)=0.42 (hexanes/EtOAc4:1 (v/v)). NMR Spectroscopy: ¹H NMR (500 MHz, CDCl₃, 25° C., δ): 8.32(d, J=9.2 Hz, 1H), 7.42-7.41 (m, 1H), 7.40 (s, 1H), 7.37 (br. s, 1H),2.22 (s, 3H). ¹³C NMR (125 MHz, CDCl₃, 25° C., δ): 168.3, 138.2, 130.8,129.9, 123.6, 123.1, 120.6 (q, J=259.2 Hz), 115.9, 25.0. ¹⁹F NMR (376MHz, CDCl₃, 25° C., δ): −58.2 (s). Mass Spectrometry: HRMS (ESI-TOF)(m/z): calcd for C₉H₈NO₂F₃Br ([M+H]⁺), 297.9690, found, 297.9692.

N-(4-Iodo-2-(trifluoromethoxy)phenyl)acetamide (3h)

A solution of N-(4-iodophenyl)-N-(trifluoromethoxy)acetamide (2h) (138mg, 0.400 mmol) in MeNO₂ (0.400 mL, 1.00 M) was heated at 80° C. underN₂ atmosphere for 13 h. The reaction mixture was concentrated in vacuo.The residue was purified by chromatography on silica gel, eluting withhexanes:EtOAc (4:1 to 2:3 (v/v)), to afford the title compound as abeige solid (108 mg, 0.313 mmol, 78% yield). R_(f)=0.46 (hexanes/EtOAc4:1 (v/v)). NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃, ° C., δ): 8.19 (d,J=8.6 Hz, 1H), 7.59 (dd, J=8.8, 1.5 Hz, 1H), 7.56 (s, 1H), 7.36 (br. s,1H), 2.22 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 168.3, 138.0,136.8, 130.7, 129.2, 123.4, 120.6 (q, J=259.1 Hz), 85.6, 25.0. ¹⁹F NMR(376 MHz, CDCl₃, 25° C., δ): −58.3 (s). Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₉H₈NO₂F₃I ([M+H]), 345.9552, found,345.9548.

N-(5-Fluoro-2-(trifluoromethoxy)phenyl)acetamide (3i) andN-(3-fluoro-2-(trifluoromethoxy)phenyl)acetamide (3i-II)

A solution of N-(3-fluorophenyl)-N-(trifluoromethoxy)acetamide (2i)(95.9 mg, 0.400 mmol) in MeNO₂ (0.400 mL, 1.00 M) was heated at 120° C.under N₂ atmosphere for 20 h. The reaction mixture was purified bypreparative TLC using hexanes:EtOAc (7:3 (v/v)) for development. Thepurification afforded 3i (51.2 mg, 0.216 mmol, 54% yield) and 3i-II(31.5 mg, 0.132 mmol, 33% yield). Data for 3i: white solid; R_(f)=0.67(hexanes/EtOAc 7:3 (v/v)). NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃, 25°C., δ): 8.25 (d, J=9.0 Hz, 1H), 7.47 (br. s, 1H), 7.23-7.18 (m, 1H),6.83-6.73 (m, 1H), 2.23 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ):168.4, 161.0 (d, J=243.9 Hz), 133.7, 132.2 (d, J=12.1 Hz), 121.8 (d,J=9.7 Hz), 120.7 (q, J=258.0 Hz), 110.6 (d, J=24.1 Hz), 109.1 (d, J=29.6Hz), 25.0. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −58.5 (s), −111.9 (q).Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₉H₈NO₂F₄ ([M+H]⁺),238.0491, found, 238.0492. Data for 3i-II: white solid; R_(f)=0.56(hexanes/EtOAc 7:3 (v/v)). NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃, 25°C., δ): 8.15 (d, J=7.7 Hz, 1H), 7.41 (br. s, 1H), 7.29-7.23 (m, 1H),6.93 (t, J=9.0 Hz, 1H), 2.23 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C.,δ): 168.4, 155.2 (d, J=250.3 Hz), 133.5, 128.6 (d, J=8.5 Hz), 126.3 (d,J=13.8 Hz), 121.0 (q, J=259.9 Hz), 117.3, 111.9 (d, J=18.3 Hz), 24.9.¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −58.9 (d), −127.3 (s). MassSpectrometry: HRMS (ESI-TOF) (m/z): calcd for C₉H₈NO₂F₄ ([M+H]⁺),238.0491, found, 238.0490.

N-(2-Bromo-6-(trifluoromethoxy)phenyl)acetamide (3j)

A solution of N-(2-bromophenyl)-N-(trifluoromethoxy)acetamide (2j) (119mg, 0.400 mmol) in MeNO₂ (0.400 mL, 1.00 M) was heated at 80° C. underN₂ atmosphere for 11 h. The reaction mixture was purified by preparativeTLC using hexanes:EtOAc (3:2 (v/v)) for development. The purificationafforded the title compound as a white crystalline solid (103 mg, 0.346mmol, 87% yield). R_(f)=0.62 (hexanes/EtOAc 3:2 (v/v)). NMRSpectroscopy: ¹H NMR (700 MHz, (CD₃)₂SO, 25° C., δ): 9.80 (br. s, 1H),7.73 (d, J=8.2 Hz, 1H), 7.46 (d, J=8.2 Hz, 1H), 7.26 (t, J=8.2 Hz, 1H),2.04 (s, 3H). ¹³C NMR (175 MHz, (CD₃)₂SO, 25° C., δ): 168.2, 145.7,131.6, 130.5, 129.4, 124.2, 120.8, 119.9 (q, J=256.5 Hz), 22.4. ¹⁹F NMR(376 MHz, (CD₃)₂SO, 25° C., δ): −58.6 (s). Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₉H₈NO₂F₃Br ([M+H]⁺), 297.9690, found,297.9693.

N-(5-Methoxy-2-(trifluoromethoxy)-3-(trifluoromethyl) phenyl) acetamide(3k) andN-(3-methoxy-2-(trifluoromethoxy)-5-(trifluoromethyl)phenyl)acetamide(3k-II)

A solution ofN-(3-methoxy-5-(trifluoromethyl)phenyl)-N-(trifluoro-methoxy)acetamide(2k) (127 mg, 0.400 mmol) in MeNO₂ (0.400 mL, 1.00 M) was heated at 120°C. under N₂ atmosphere for 20 h. The reaction mixture was purified bypreparative TLC using hexanes:EtOAc (7:3 (v/v)) for development. Thepurification afforded 3k (49.2 mg, 0.155 mmol, 39% yield) and 3k-II(37.7 mg, 0.119 mmol, 31% yield). Data for 3k: beige solid; R_(f)=0.56(hexanes/EtOAc 3:2 (v/v)). NMR Spectroscopy: ¹H NMR (500 MHz, CDCl₃, 25°C., δ): 8.15 (br. s, 1H), 7.49 (br. s, 1H), 6.91 (d, J=3.1 Hz, 1H), 3.84(s, 3H), 2.22 (s, 3H). ¹³C NMR (125 MHz, CDCl₃, 25° C., δ): 168.5,158.5, 134.0, 128.7, 125.6 (q, J=32.4 Hz), 122.3 (q, J=271.9 Hz), 120.9(q, J=260.0 Hz), 110.4, 108.8 (q, J=4.3 Hz), 56.1, 24.8. ¹⁹F NMR (376MHz, CDCl₃, 25° C., δ): −56.2 (q), −61.3 (q). Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₁₁H₁₀NO₃F₆ ([M+H]⁺), 318.0565, found,318.0556. Data for 2k-II: beige solid; R_(f)=0.72 (hexanes/EtOAc 3:2(v/v)). NMR Spectroscopy: ¹H NMR (500 MHz, CDCl₃, 25° C., δ): 8.35 (br.s, 1H), 7.46 (br. s, 1H), 6.95 (d, J=1.8 Hz, 1H), 3.93 (s, 3H), 2.23 (s,3H). ¹³C NMR (125 MHz, CDCl₃, 25° C., δ): 168.5, 153.0, 133.5, 130.6 (q,J=32.9 Hz), 129.3, 123.5 (q, J=271.5 Hz), 121.0 (q, J=260.1 Hz), 110.9,104.7, 56.6, 24.9. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −57.7 (s), −63.4(s). Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₁₁H₁₀NO₃F₆([M+H]⁺), 318.0565, found, 318.0555.

N-(2-(Trifluoromethoxy)-5-(trifluoromethyl)phenyl)acetamide (3l) andN-(2-(trifluoromethoxy)-3-(trifluoromethyl)phenyl)acetamide (3l-II)

A solution of N-(trifluoromethoxy)-N-(3-(trifluoromethyl)phenyl)acetamide (21) (115 mg, 0.400 mmol) in MeNO₂ (0.400 mL, 1.00 M) washeated at 140° C. under N₂ atmosphere for 20 h. The reaction mixture waspurified by preparative TLC using hexanes:EtOAc (4:1 (v/v)) fordevelopment (prep TLC was developed twice). The purification afforded 31(53.5 mg, 0.186 mmol, 47% yield) and 3l-II (37.4 mg, 0.129 mmol, 33%yield). Data for 3l: white solid; R_(f)=0.66 (hexanes/EtOAc 7:3 (v/v)).NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃, 25° C., δ): 8.79 (br. s, 1H),7.55 (br. s, 1H), 7.32-7.39 (m, 2H), 2.26 (s, 3H). ¹³C NMR (175 MHz,CDCl₃, 25° C., δ): 168.6, 139.9, 131.1, 129.9 (q, J=33.1 Hz), 123.5 (q,J=270.8 Hz), 121.1, 120.5 (q, J=259.6 Hz), 120.1, 119.2, 24.9. ¹⁹F NMR(376 MHz, CDCl₃, 25° C., δ): −58.0 (s), −63.2 (s). Mass Spectrometry:HRMS (ESI-TOF) (m/z): calcd for C₁₀H₈NO₂F₆ ([M+H]⁺), 288.0459, found,288.0457. Data for 3l-II: white solid; R_(f)=0.43 (hexanes/EtOAc 7:3(v/v)). NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃, 25° C., δ): 8.52 (br.s, 1H), 7.50 (br. s, 1H), 7.39-7.46 (m, 2H), 2.23 (s, 3H). ¹³C NMR (175MHz, CDCl₃, 25° C., δ): 168.5, 135.7, 133.1, 128.3, 126.7, 125.2 (q,J=32.0 Hz), 122.6 (d, J=5.3 Hz), 122.5 (q, J=271.6 Hz), 120.7 (q,J=260.3 Hz), 24.7. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −55.7 (d), −61.1(q). Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₁₀H₈NO₂F₆([M+H]⁺), 288.0459, found, 288.0463.

N-(5-Methoxy-2-(trifluoromethoxy)phenyl)acetamide (3m) andN-(3-methoxy-2-(trifluoromethoxy)phenyl)acetamide (3m-II)

A solution of N-(3-methoxyphenyl)-N-(trifluoromethoxy)acetamide (2m)(99.7 mg, 0.400 mmol) in MeNO₂ (0.400 mL, 1.00 M) was heated at 80° C.under N₂ atmosphere for 15 h. The reaction mixture was purified bypreparative TLC using hexanes:EtOAc (4:1 (v/v)) for development (prepTLC was developed four times). The purification afforded 3m (55.3 mg,0.222 mmol, 55% yield) and 3m-II (14.9 mg, 0.0600 mmol, 15% yield). Datafor 3m: white solid; R_(f)=0.77 (hexanes/EtOAc 3:2 (v/v)). NMRSpectroscopy: ¹H NMR (400 MHz, CDCl₃, 25° C., δ): 8.02 (d, J=2.0 Hz,1H), 7.48 (br. s, 1H), 7.12 (dd, J=9.2, 1.1 Hz, 1H), 6.59 (dd, J=9.0,3.0 Hz, 1H), 3.79 (s, 3H), 2.21 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, ° C.,δ): 168.5, 158.5, 131.8, 131.6, 121.7, 120.8 (q, J=256.8 Hz), 109.9,106.8, 55.8, 24.9. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −58.7 (s). MassSpectrometry: HRMS (ESI-TOF) (m/z): calcd for C₁₀H₁₁NO₃F₃ ([M+H]⁺),250.0691, found, 250.0690. Data for 3m-II: white solid; R_(f)=0.70(hexanes/EtOAc 3:2 (v/v)). NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃, 25°C., δ): 7.93 (d, J=8.2 Hz, 1H), 7.40 (br. s, 1H), 7.23 (t, J=8.4 Hz,1H), 6.73 (d, J=8.2 Hz, 1H), 3.87 (s, 3H), 2.21 (s, 3H). ¹³C NMR (175MHz, CDCl₃, 25° C., δ): 168.4, 152.7, 132.9, 128.2, 127.6, 121.1 (q,J=258.7 Hz), 113.8, 108.0, 56.3, 24.9. ¹⁹F NMR (376 MHz, CDCl₃, 25° C.,δ): −57.9 (s). Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd forC₁₀H₁₁NO₃F₃ ([M+H]⁺), 250.0691, found, 250.0692.

Methyl 3-acetamido-4-(trifluoromethoxy)benzoate (3n) and methyl3-acetamido-2-(trifluoromethoxy)benzoate (3n-II)

A solution of methyl 3-(N-(trifluoromethoxy)acetamido)benzoate (2n) (111mg, 0.400 mmol) in MeNO₂ (0.400 mL, 1.00 M) was heated at 120° C. underN₂ atmosphere for 20 h. The reaction mixture was purified by preparativeTLC using Et₂O for development. The purification afforded 90.4 mg of a1.14:1 mixture of 3n and 3n-II (81% overall yield). Compounds 3n and3n-II were further separated for characterization by preparative TLC(eluting twenty times with hexanes:Et₂O (7:3 (v/v)). Data for 3n: whitesolid; R_(f)=0.59 (hexanes/EtOAc 3:2 (v/v)). NMR Spectroscopy: ¹H NMR(400 MHz, CDCl₃, 25° C., δ): 9.02 (br. s, 1H), 7.82 (dd, J=8.5, 2.0 Hz,1H), 7.41 (br. s, 1H), 7.31 (dd, J=8.7, 1.6 Hz, 1H), 3.92 (s, 3H), 2.25(s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 168.4, 166.0, 141.2,130.3, 129.4, 125.9, 123.4, 120.5 (q, J=259.1 Hz), 119.5, 52.6, 24.9.¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −57.8 (s). Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₁₁H₁₁NO₄F₃ ([M+H]⁺), 278.0640, found,278.0640.

Data for 3n-II: white solid; R_(f)=0.56 (hexanes/EtOAc 3:2 (v/v)). NMRSpectroscopy: ¹H NMR (700 MHz, CDCl₃, 25° C., δ): 8.56 (d, J=8.2 Hz,1H), 7.66 (d, J=7.7 Hz, 1H), 7.51 (br. s, 1H), 7.39 (t, J=8.0 Hz, 1H),3.93 (s, 3H), 2.24 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 168.5,165.0, 136.5, 132.8, 128.1, 126.6, 126.2, 126.1, 120.8 (q, J=258.6 Hz),52.7, 24.9. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −57.5 (s). MassSpectrometry: HRMS (ESI-TOF) (m/z): calcd for C₁₁H₁₁NO₄F₃ ([M+H]⁺),278.0640, found, 278.0639.

N-(6-Chloro-2-(trifluoromethoxy)-3-(trifluoromethyl)phenyl) acetamide(3o)

A solution ofN-(2-chloro-5-(trifluoromethyl)phenyl)-N-(trifluoro-methoxy)acetamide(2o) (129 mg, 0.400 mmol) in MeNO₂ (0.400 mL, 1.00 M) was heated at 140°C. under N₂ atmosphere for 20 h. The reaction mixture was purified bypreparative TLC using hexanes:EtOAc (1:19 (v/v)) for development (prepTLC was developed five times). The purification afforded the titlecompounds as a white solid (96.0 mg, 0.299 mmol, 75% yield). The productwas obtained as a 5:3 mixture of atropisomers. The spectral datacorresponds to the major atropisomer. R_(f)=0.41 (hexanes/EtOAc 19:1(v/v)). NMR Spectroscopy: ¹H NMR (500 MHz, CDCl₃, 25° C., δ): 7.70 (d,J=8.9 Hz, 1H), 7.36 (d, J=8.9 Hz, 1H), 6.89 (br. s, 1H), 2.25 (br. s,3H). ¹³C NMR (125 MHz, CDCl₃, 25° C., δ): 168.4, 148.4, 132.3, 129.5,127.9 (q, J=32.2 Hz), 126.8, 122.3 (q, J=271.9 Hz), 120.4 (q, J=259.5Hz), 118.7, 23.1. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −57.9 (s), −63.2(s). Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₁₀H₇NO₂F₆Cl([M+H]⁺), 322.0070, found, 322.0068.

N-(3-Benzyl-8-chloro-4-oxo-6-(trifluoromethoxy)−3,4-dihydroquinazolin-7-yl)acetamide (3p)

A solution ofN-(3-benzyl-8-chloro-4-oxo-3,4-dihydroquinazolin-7-yl)-N-(trifluoromethoxy)acetamide(2p) (120 mg, 0.291 mmol) in MeNO₂ (0.582 mL, 0.500 M) was heated at 50°C. under N₂ atmosphere for 14 h. The reaction mixture was concentratedin vacuo. The residue was purified by chromatography on silica gel,eluting with hexanes:EtOAc (2:3 (v/v)), to afford the title compound asa white solid (89.0 mg, 0.216 mmol, 74% yield). R_(f)=0.73(hexanes/EtOAc 3:2 (v/v)). NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃, 25°C., δ): 8.07 (s, 1H), 7.81 (s, 1H), 7.39-7.30 (m, 5H), 7.03 (br. s, 1H),5.17 (s, 2H), 2.26 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 168.6,157.3, 148.7, 148.4, 143.9, 139.7, 135.2, 129.3, 128.7, 128.6, 128.3,128.2, 120.6 (q, J=258.8 Hz), 116.3, 49.7, 23.2. ¹⁹F NMR (376 MHz,CDCl₃, 25° C., δ): −57.1 (s). Mass Spectrometry: HRMS (ESI-TOF) (m/z):calcd for C₁₈H₁₄N₃O₃Cl F₃ ([M+H]⁺), 412.0676, found, 412.0673.

Methyl 4-acetamido-3-(trifluoromethoxy)benzoate (3q)

A solution of methyl 4-(N-(trifluoromethoxy)acetamido)benzoate (2q) (111mg, 0.400 mmol) in MeNO₂ (0.400 mL, 1.00 M) was heated at 120° C. underN₂ atmosphere for 20 h. The reaction mixture was concentrated in vacuo.The residue was purified by chromatography on silica gel, eluting withhexanes:EtOAc (9:1 to 7:3 (v/v)), to afford the title compound as awhite solid (97.1 mg, 0.350 mmol, 87% yield). R_(f)=0.51 (hexanes/EtOAc4:1 (v/v)). NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃, 25° C., δ): 8.56(d, J=8.6 Hz, 1H), 7.97 (d, J=8.6 Hz, 1H), 7.93 (s, 1H), 7.56 (br. s,1H), 3.92 (s, 3H), 2.27 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ):168.5, 165.6, 137.2, 134.7, 129.3, 125.8, 121.5, 120.8, 120.6 (q,J=258.9 Hz), 52.5, 25.2. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −58.1 (s).Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₁₁H₁₁NO₄F₃ ([M+H]⁺),278.0640, found, 278.0643.

Methyl 4-benzamido-3-(trifluoromethy)benzoate (3r)

A solution of methyl 4-(N-(trifluoromethoxy)benzamido)benzoate (2r) (136mg, 0.400 mmol) in MeNO₂ (0.400 mL, 1.00 M) was heated at 120° C. underN₂ atmosphere for 20 h. The reaction mixture was concentrated in vacuo.The residue was purified by chromatography on silica gel, eluting withhexanes:EtOAc (9:1 to 7:3 (v/v)), to afford the title compound as awhite solid (107 mg, 0.315 mmol, 79% yield). The reaction also affordedmethyl 2-phenyl-4-(trifluoromethoxy)benzo[d]oxazole-6-carboxylate (4r)as a white solid (5.4 mg, 0.016 mmol, 4% yield). Data for 3r: R_(f)=0.72(hexanes/EtOAc 7:3 (v/v)). NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃, 25°C., δ): 8.74 (d, J=8.6 Hz, 1H), 8.37 (br. s, 1H), 8.04 (dd, J=8.6, 1.7Hz, 1H), 7.98 (s, 1H), 7.90-7.84 (m, 2H), 7.63-7.58 (m, 1H), 7.56-7.51(m, 2H), 3.93 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 165.6,165.5, 137.7, 135.0, 134.2, 132.8, 129.5, 129.3, 127.2, 126.0, 121.7,120.8, 120.7 (q, J=259.1 Hz), 52.5. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ):−58.1 (s). Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd forC₁₆H₁₃NO₄F₃ ([M+H]⁺), 340.0797, found, 340.0793. Data for 4r: R_(f)=0.73(hexanes/EtOAc 4:1 (v/v)). NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃, 25°C., δ): 8.36-8.25 (m, 3H), 8.10 (d, J=8.2 Hz, 1H), 7.79 (d, J=8.2 Hz,1H), 7.65-7.49 (m, 3H), 3.97 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C.,δ): 166.8, 165.7, 150.6, 146.2, 132.4, 129.2, 128.1, 127.3, 126.8,126.6, 119.7, 112.4, 52.5.

Methyl 4-((methoxycarbonyl)amino)-3-(trifluoromethoxy)benzoate (3s)

A solution of methyl 4-((methoxycarbonyl)(trifluoromethoxy)amino)benzoate (2s) (130 mg, 0.443 mmol) in MeNO₂ (0.443 mL, 1.00 M) washeated at 120° C. under N₂ atmosphere for 20 h. The reaction mixture waspurified by preparative TLC using hexanes:EtOAc (19:1 (v/v)) fordevelopment (prep TLC was developed three times). The purificationafforded the title compound as a white crystalline solid (106 mg, 0.362mmol, 82% yield). R_(f)=0.63 (hexanes/EtOAc 4:1 (v/v)). NMRSpectroscopy: ¹H NMR (700 MHz, CDCl₃, 25° C., δ): 8.33 (d, J=8.60 Hz,1H), 7.97 (dd, J=8.6, 1.7 Hz, 1H), 7.92 (s, 1H), 7.13 (br. s, 1H), 3.91(s, 3H), 3.83 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 165.7,153.3, 136.9, 135.0, 129.4, 125.0, 121.7, 120.6 (q, J=258.9 Hz), 119.1,53.0, 52.5. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −58.2 (s). MassSpectrometry: HRMS (ESI-TOF) (m/z): calcd for C₁₁H₁₁NO₅F₃ ([M+H]⁺),294.0589, found, 294.0587.

Methyl 4-(3,3-dimethylureido)-3-(trifluoromethoxy)benzoate (3t)

A solution of methyl 4-(3,3-dimethyl-1-(trifluoromethoxy)ureido)benzoate (2t) (43.6 mg, 0.142 mmol) in MeNO₂ (0.142 mL, 1.00 M) washeated at 120° C. under N₂ atmosphere for 20 h. The reaction mixture waspurified by preparative TLC using hexanes:EtOAc (7:3 (v/v)) fordevelopment (prep TLC was developed twice). The purification affordedthe title compound as a colorless oil (25.7 mg, 0.0839 mmol, 59% yield).R_(f)=0.58 (hexanes/EtOAc 1:1 (v/v)). NMR Spectroscopy: ¹H NMR (700 MHz,CDCl₃, 25° C., δ): 8.42 (d, J=8.6 Hz, 1H), 7.93 (d, J=9.0 Hz, 1H), 7.88(s, 1H), 6.98 (br. s, 1H), 3.89 (s, 3H), 3.06 (s, 6H). ¹³C NMR (175 MHz,CDCl₃, 25° C., δ): 165.9, 154.3, 136.9, 136.6, 129.4, 124.0, 121.7,120.7 (q, J=258.4 Hz), 119.6, 52.3, 36.5. ¹⁹F NMR (376 MHz, CDCl₃, 25°C., δ): −58.2 (s). Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd forC₁₂H₁₄N₂O₄F₃ ([M+H]⁺), 307.0906, found, 307.0902.

Example 4. One-Pot Method

Next, it was explored as to whether the two-step sequence could beconverted into a one-pot transformation to further simplify the reactionprotocol. Exposure of 1u to Togni reagent II and NaH in CH₂Cl₂ at roomtemperature provided the desired product 3u in 70% isolated yield(Scheme 4). These reaction conditions tolerate α-amino acid ester (3v),quinoline (3w), and indole (3x). Moreover, products from Scheme 3 suchas 3a, 3c, 3g, and 3q can be directly obtained from the correspondinghydroxylamines via a one-pot reaction protocol without the isolation ofintermediates 2. However removal of CH₂Cl₂ at the end of thetrifluoromethylation reaction followed by re-dissolving the resultingresidue in MeNO₂ is needed, because the OCF₃-migration for thesesubstrates requires higher reaction temperature.

N-(4-Methyl-2-(trifluoromethoxy)phenyl)acetamide (3u)

Under N₂ atmosphere, to a mixture of N-hydroxy-N-(p-tolyl)acetamide (1u)(78.2 mg, 0.473 mmol, 1.00 equiv) and NaH (13.6 mg, 0.568 mmol, 1.20equiv) in CH₂Cl₂ (4.73 mL, 0.100 M) was added Togni reagent II (179 mg,0.568 mmol, 1.2 equiv) and the reaction mixture was stirred at rt for 23h. The reaction mixture diluted with CH₂Cl₂ (30 mL) and washed withwater (30 mL). The layers were separated, the organic layer was dried(MgSO₄), filtered and concentrated in vacuo. The residue was purified bypreparative TLC using hexanes:EtOAc (4:1 (v/v)) for development (prepTLC was developed twice). The purification afforded the title compoundas a white solid (76.8 mg, 0.329 mmol, 70% yield). R_(f)=0.42(hexanes/EtOAc 4:1 (v/v)). NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃, 25°C., δ): 8.21 (d, J=8.2 Hz, 1H), 7.31 (br. s, 1H), 7.08 (d, J=8.2 Hz,1H), 7.05 (br. s, 1H), 2.33 (s, 3H), 2.21 (s, 3H). ¹³C NMR (175 MHz,CDCl₃, 25° C., δ): 168.3, 138.2, 134.7, 128.2, 128.0, 122.2, 120.9,120.7 (q, J=257.4 Hz), 24.8, 21.0. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ):−58.0 (s). Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd forC₁₀H₁₁NO₂F₃ ([M+H]⁺), 234.0742, found, 234.0737.

Methyl (R)-2-acetamido-3-(4-acetamido-3-(trifluoromethoxy)phenyl)propanoate (3v)

Under N₂ atmosphere, to a mixture of methyl(R)-2-acetamido-3-(4-(N-hydroxyacetamido)phenyl)propanoate (1v) (100 mg,0.340 mmol, 1.00 equiv) and NaH (9.80 mg, 0.410 mmol, 1.20 equiv) inCH₂Cl₂ (3.40 mL, 0.100 M) was added Togni reagent II (128.8 mg, 0.410mmol, 1.20 equiv) and the reaction mixture was stirred at rt for 13 h.The reaction mixture was then heated to 50° C. for 24 h. The reactionwas quenched with water, extracted with CH₂Cl₂, dried (MgSO₄), filteredand concentrated in vacuo. The residue was purified by chromatography onsilica gel, eluting with hexanes:EtOAc (1:1 to 1:3 (v/v)), and thenrecrystallized from hexanes/CH₂Cl₂ to afford the title compound as aslighty yellow solid (63.0 mg, 0.174 mmol, 51% yield). R_(r)=0.12(hexanes/EtOAc 1:1 (v/v)). NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃, 25°C., δ): 8.31 (d, J=8.4 Hz, 1H), 7.37 (s, 1H), 7.00 (d, J=8.4 Hz, 1H),6.98 (s, 1H), 5.96 (d, J=7.0 Hz, 1H), 4.86 (dd, J=5.6, 12.8 Hz, 1H),3.73 (s, 3H), 3.15 (dd, J=5.6, 14.0 Hz, 1H), 3.08 (dd, J=5.6, 14.0 Hz,1H), 2.22 (s, 3H), 2.00 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ):171.8, 169.8, 168.4, 138.0, 132.5, 129.6, 128.6, 122.1, 121.2, 120.7 (q,J=147.4 Hz), 53.2, 52.6 (d, J=14.0 Hz), 37.3, 25.0, 23.3. ¹⁹F NMR (376MHz, CDCl₃, 25° C., δ): −57.7 (s). Mass Spectrometry: HRMS (ESI-TOF)(m/z): calcd for C₁₅H₁₈N₂O₅F₃ ([M+H]⁺), 363.1168, found, 363.1164.

Methyl hydroxy(7-(trifluoromethoxy)quinolin-8-yl)carbamate (3w)

Under N₂ atmosphere, to a mixture of methylhydroxy(quinolin-8-yl)carbamate (1w) (100 mg, 0.458 mmol, 1.00 equiv)and NaH (13.2 mg, 0.550 mmol, 1.20 equiv) in CH₂Cl₂ (4.58 mL, 0.100 M)was added Togni reagent II (173.6 mg, 0.550 mmol, 1.20 equiv) and thereaction mixture was stirred at rt for 13 h. The reaction was thenheated to 50° C. for 24 h. The reaction was quenched with water,extracted with CH₂Cl₂, dried (MgSO₄), filtered and concentrated invacuo. The residue was purified by chromatography on silica gel, elutingwith hexanes:EtOAc (5:1 to 3:1 (v/v)), to afford the title compound as abrown solid (81.0 mg, 0.283 mmol, 61% yield). R_(f)=0.21 (hexanes/EtOAc4:1 (v/v)). NMR Spectroscopy: ¹H NMR (400 MHz, CDCl₃, 25° C., δ): 8.92(dd, J=1.4, 4.1 Hz, 1H), 8.18 (dd, J=1.4, 8.3 Hz, 1H), 7.83 (s, 1H),7.69 (d, J=9.1 Hz, 1H), 7.54 (d, J=9.1 Hz, 1H), 7.48 (dd, J=4.2, 8.3 Hz,1H), 3.83 (s, 3H). ¹³C NMR (125 MHz, (CD₃)₂SO, δ): 154.6, 150.6, 143.0,142.1, 136.3, 126.9, 126.8, 125.4, 122.1, 121.4, 120.9 (q, J=257.4 Hz),53.2. ¹⁹F NMR (376 MHz, CDCl₃, (376 MHz, CDCl₃, 25° C., δ): −56.8 (s).Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₁₂H₁₀N₂O₃F₃([M+H]⁺), 287.0644, found, 287.0639.

N-(1-(phenylsulfonyl)-4-(trifluoromethoxy)-1H-indol-5-yl)acetamide (3x)

Under N₂ atmosphere, to a mixtureN-hydroxy-N-(1-(phenylsulfonyl)-1H-indol-5-yl)acetamide (1x) (132 mg,0.400 mmol, 1.00 equiv) and NaH (11.5 mg, 0.480 mmol, 1.20 equiv) inCH₂Cl₂ (4.00 mL, 0.100 M) was added Togni reagent II (152 mg, 0.480mmol, 1.2 equiv) and the reaction mixture was stirred at rt for 23 h.The reaction mixture diluted with CH₂Cl₂ (30 mL) and washed with water(30 mL). The layers were separated, the organic layer was dried (MgSO₄),filtered and concentrated in vacuo. The residue was purified bypreparative TLC using hexanes:EtOAc (3:2 (v/v)) for development (prepTLC was developed twice). The purification afforded the title compoundas an off-white solid (108 mg, 0.271 mmol, 68% yield). R_(f)=0.24(hexanes/EtOAc 7:3 (v/v)). NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃, 25°C., δ): 8.13 (d, J=9.0 Hz, 1H), 7.93 (d, J=9.0 Hz, 1H), 7.89 (d, J=7.3Hz, 2H), 7.63-7.54 (m, 2H), 7.52-7.43 (m, 2H), 7.33 (br. s, 1H), 6.70(br. s, 1H), 2.22 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 168.6,138.0, 134.4, 132.8, 131.2, 129.7, 127.9, 127.1, 127.0, 125.2, 121.2 (q,J=258.8 Hz), 120.4, 113.2, 105.7, 24.6. ¹⁹F NMR (376 MHz, CDCl₃, 25° C.,δ): −57.9 (s). Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd forC₁₇H₁₄N₂O₄SF₃ ([M+H]⁺), 399.0626, found, 399.0625.

N-(4-bromo-2-(trifluoromethoxy)phenyl)acetamide (3g)

Under N₂ atmosphere, to a mixture ofN-(4-bromophenyl)-N-hydroxyacetamide (1g) (11.5 mg, 0.0502 mmol, 1.00equiv) and NaH (1.4 mg, 0.060 mmol, 1.2 equiv) in CH₂Cl₂ (0.500 mL,0.100 M) was added Togni reagent II (19.0 mg, 0.0600 mmol, 1.2 equiv).The resulting mixture was stirred at rt for 15 h and was thenconcentrated in vacuo. MeNO₂ (0.500 mL) was added and the reactionmixture was stirred at 80° C. for 15 h. Trifluorotoluene (6.14 μL, 0.050mmol, 1.00 equiv) and CDCl₃ (0.250 mL) were added and the reactionmixture was analyzed by ¹⁹F NMR. The ¹⁹F NMR analysis indicated 72%yield of the desired product.

N-(4-acetyl-2-(trifluoromethoxy)phenyl)acetamide (3c)

Under N₂ atmosphere, to a mixture ofN-(4-acetylphenyl)-N-hydroxyacetamide (1c) (9.7 mg, 0.050 mmol, 1.0equiv) and NaH (1.4 mg, 0.060 mmol, 1.2 equiv) in CH₂Cl₂ (0.500 mL,0.100 M) was added Togni reagent II (19.0 mg, 0.0600 mmol, 1.2 equiv).The resulting mixture was stirred at rt for 15 h and was thenconcentrated in vacuo. MeNO₂ (0.500 mL) was added and the reactionmixture was stirred at 120° C. for 15 h. Trifluorotoluene (6.14 μL,0.050 mmol, 1.00 equiv) and CDCl₃ (0.250 mL) were added and the reactionmixture was analyzed by ¹⁹F NMR. The ¹⁹F NMR analysis indicated 68%yield of the desired product.

N-(2-(Trifluoromethoxy)phenyl)acetamide (3a) andN-(4-(trifluoromethoxy)phenyl)acetamide (3a-II)

Under N₂ atmosphere, to a mixture of N-hydroxy-N-phenylacetamide (1a)(7.6 mg, 0.050 mmol, 1.0 equiv) and NaH (1.4 mg, 0.060 mmol, 1.2 equiv)in CH₂Cl₂ (0.500 mL, 0.100 M) was added Togni reagent II (19.0 mg,0.0600 mmol, 1.2 equiv). The resulting mixture was stirred at rt for 15h and was then concentrated in vacuo. MeNO₂ (0.500 mL) was added and thereaction mixture was stirred at 80° C. for 15 h. Trifluorotoluene (6.14μL, 0.050 mmol, 1.00 equiv) and CDCl₃ (0.250 mL) were added and thereaction mixture was analyzed by ¹⁹F NMR. The ¹⁹F NMR analysis indicated66% yield of the desired product.

Methyl 4-acetamido-3-(trifluoromethoxy)benzoate (3q)

Under N₂ atmosphere, to a mixture of methyl4-(N-hydroxyacetamido)benzoate (1q) (10.5 mg, 0.0500 mmol, 1.00 equiv)and NaH (1.4 mg, 0.060 mmol, 1.2 equiv) in CH₂Cl₂ (0.500 mL, 0.100 M)was added Togni reagent II (19.0 mg, 0.0600 mmol, 1.2 equiv). Theresulting mixture was stirred at rt for 15 h and was then concentratedin vacuo. MeNO₂ (0.500 mL) was added and the reaction mixture wasstirred at 120° C. for 15 h. Trifluorotoluene (6.14 μL, 0.050 mmol, 1.00equiv) and CDCl₃ (0.250 mL) were added and the reaction mixture wasanalyzed by ¹⁹F NMR. The ¹⁹F NMR analysis indicated 89% yield of thedesired product.

Example 5. Gram Scale Synthesis

To demonstrate the practicality and effectiveness of the approach forthe synthesis of o-OCF₃ aniline derivatives, the trifluoro-methoxylationreaction of 1q and OCF₃-migration of 2q on a gram scale was performed(Scheme 5). Reaction of 2.00 g (9.56 mmol) of 1q with 1.2 equiv Tognireagent II in the presence of 10 mol % Cs₂CO₃ in degassed chloroformgave 2q (2.51 g) in 95% isolated yield. Heating 2.51 g (9.49 mmol) of 2qin MeNO₂ at 120° C. afforded 3q (2.13 g) in 85% isolated yield.

Methyl 4-(N-(trifluoromethoxy)acetamido)benzoate (2q)

Under N₂ atmosphere, to a mixture of methyl4-(N-hydroxyacetamido)benzoate (1q) (2.00 g, 9.56 mmol, 1.00 equiv) andCs₂CO₃ (311 mg, 0.956 mmol, 10 mol %) in CHCl₃ (95.6 mL, 0.100 M) wasadded Togni reagent II (3.63 g, 11.5 mmol, 1.20 equiv) and the reactionmixture was stirred at rt for 24 h. The reaction mixture was then washedwith sat. aq. NaHCO₃ (100 mL) and the layers were separated. The organiclayer was dried (MgSO₄), filtered, and concentrated in vacuo. Theresidue was purified by chromatography on silica gel, eluting withhexanes:CH₂Cl₂ (7:3 to 0:1 (v/v)). The purification afforded the titlecompound (2.51 g, 9.05 mmol, 95% yield), which was spectroscopicallyidentical to the compound prepared according to the standard procedure(vide supra).

Methyl 4-acetamido-3-(trifluoromethoxy)benzoate (3q)

A solution of methyl 4-(N-(trifluoromethoxy)acetamido)benzoate (2q)(2.51 g, 9.05 mmol) in MeNO₂ (9.05 mL, 1.00 M) was heated at 120° C.under N₂ atmosphere for 20 h. The reaction mixture was concentrated invacuo. The residue was purified by chromatography on silica gel, elutingwith hexanes:EtOAc (9:1 to 7:3 (v/v)), to afford the title compound(2.13 g, 7.68 mmol, 85% yield), which was spectroscopically identical tothe compound prepared according to the standard procedure (vide supra).

Example 6. Trifluoromethoxylation of Heteroaryl Substrates

The effectiveness of this approach was also explored using heteroarylsubstrates. For the synthesis of o-OCF₃ pyridino derivatives, thetrifluoromethoxylation reaction of 5 and OCF₃-migration of 6 on a gramwas performed (Scheme 6). Reaction of 5 with 1.2 equiv Togni reagent IIin the presence of 10 mol % Cs₂CO₃ in degassed chloroform gave 6 in 90%isolated yield. Heating of 6 in MeNO₂ at 120° C. for 23 hours afforded 7(2.13 g) in 85% isolated yield.

N-(5-Bromo-6-chloropyridin-3-yl)-N-(trifluoromethoxy)acetamide (6)

Under N₂ atmosphere, to a mixture ofN-(5-bromo-6-chloropyridin-3-yl)-N-hydroxyacetamide (5) (221 mg, 0.832mmol, 1.00 equiv) and Cs₂CO₃ (27.1 mg, 0.0832 mmol, 10 mol %) in CHCl₃(8.32 mL, 0.100 M) was added Togni reagent II (316 g, 0.998 mmol, 1.20equiv) and the reaction mixture was stirred at rt for 15 h. The reactionmixture was diluted with CH₂Cl₂, washed with sat. aq. NaHCO₃ (30 mL) andthe layers were separated. The organic layer was dried (MgSO₄), filteredand concentrated in vacuo. The residue was purified by chromatography onsilica gel, eluting with hexanes:CH₂Cl₂ (1:3 to 1:4 (v/v)), to afford250 mg of the title compound as a slightly yellow oil (90% yield).R=0.55 (CH₂Cl₂:hexanes 1:1). NMR Spectroscopy: ¹H NMR (500 MHz, CDCl₃,25° C., δ): 8.41 (d, J=0.85 Hz, 1H), 7.99 (d, J=0.85 Hz, 1H), 2.38 (s,3H). ¹³C NMR (125 MHz, CDCl₃, 25° C., δ): 172.8, 149.9, 143.0, 137.2,136.1, 122.7 (q, J=265.2 Hz), 120.1, 21.5. ¹⁹F NMR (376 MHz, CDCl₃, 25°C., δ): −65.1 (s).

N-(5-bromo-6-chloro-4-(trifluoromethoxy)pyridin-3-yl)acetamide (7)

A solution ofN-(5-bromo-6-chloro-2-(trifluoromethoxy)pyridin-3-yl)acetamide (6) (102mg, 0.306 mmol) in MeNO₂ (0.306 mL, 1.00 M) was heated at 120° C. underN₂ atmosphere for 23 h. The reaction mixture was purified by preparativeTLC using hexanes:EtOAc (93:7 (v/v)) for development. The purificationafforded 49 mg of the title compound as a white solid (48% yield).R_(f)=0.49 (hexanes/EtOAc 4:1 (v/v)). NMR Spectroscopy: ¹H NMR (700 MHz,CDCl₃, 25° C., δ): 9.12 (s, 1H), 7.30 (br. s, 1H), 2.27 (s, 3H). ¹³C NMR(175 MHz, CDCl₃, 25° C., δ): 168.7, 142.4, 140.4, 134.8, 123.7, 119.9(q, J=263.4 Hz), 117.4, 24.9. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −56.7(s).

Example 7. Trifluoromethoxylation of Pyridine Substrates

Herein is disclosed the first efficient and scalable one-pot protocolfor regioselective synthesis of a broad spectrum oftrifluoromethoxylated pyridines and pyrimidines using commerciallyavailable, bench-stable Togni reagent I.

Methyl (5-bromo-6-methoxypyridin-3-yl)(hydroxyl)carbamate (8a) as usedas the model substrate. This compound could be readily prepared from thecorresponding nitropyridine through a one-pot reduction/protectionprocedure. Exposure of 8a to Togni reagent II in the presence of cesiumcarbonate (0.1 equiv) in chloroform at room temperature for 15 hoursafforded the desired product 9a in only 29% yield.²⁸ Examination ofdifferent trifluoromethylation reagents such as Togni reagent I, Umemotoreagent, and Shibata-Johnson reagent²³ revealed that Togni reagent I wassuperior to other reagents and delivered the desired product 9a in 42%yield. Higher yield was obtained in the absence of Cs₂CO₃. Screening ofsolvents showed that CH₂Cl₂ gave the best result, providing the desiredproduct 9a in 87% NMR yield.

With the optimized reaction conditions in hand, the scope and generalityof the trifluoromethoxylation reaction was explored. A wide range offunctional groups and substitution patterns were tolerated (Scheme 7).Halogen functionalities, in particular Br and I, remain intact after thereaction, providing useful synthetic handles for further elaborations(9a-h, 9k, 9r, 9s, 9u, 9v). Other functional groups such as alkyl- andaryl-ethers (9i, 9k-m, 9v-x), aldehydes (9m), ketone (9x), alkene (9v),alkyne (9w), amide (9y), esters (9v-w), and benzo[1,3]dioxole (9y)proved compatible under the reaction conditions. In addition, thismethodology was successfully applied to pyridines bearing a wide arrayof heteroaryl substituents such as furan (9m), pyrazole (9n),1,2,4-triazole (9o), benzimidazole (9p), benzotriazole (9q, 9t), indole(9r, 9y), 7-azaindole (9s), thiazole (9t), and 2,6-dichloropurine (9u).More excitingly, our mild reaction conditions allow late-stagetrifluoromethoxylation of complex organic molecules. For examples,estrone and Tadalafil conjugated pyridines (8x, 8y) weretrifluoromethoxylated to afford the desired product 9x and 9y in 71% and66% yield, respectively. Remarkably, no epimerization was observed underthese mild reaction conditions. These results further demonstrated thesynthetic utility of our strategy.

Several features of the reaction are noteworthy. First of all, thereaction is sensitive to the electronic properties of substituents onpyridine. Substrates with an electron donating substituent para to theprotected N-hydroxylamine readily undergo rearrangement to yield thedesired trifluoromethoxylated products at or below room temperature(9a-b, 9i, 9k-n, 9p, 9r-s, 9v-y). In the absence of such substituents,higher reaction temperatures are required for the OCF₃-migration step(9c-h, 9o, 9q, 9t-u). These observations are consistent with theformation of nitrenium ion through heterolytic cleavage of N—O bond(vide infra).²⁴ Secondly, for the reactions that take place at or belowroom temperature, the OCF₃ group is introduced exclusively to theα′-position.²⁵ Since α- and α′-carbon of pyridines are metabolicallylabile sites, incorporation of an electron withdrawing OCF₃ group to theα′-position could improve the metabolic stability of the molecule.²⁶ Ifthe α′-position is blocked, product of γ-OCF₃ pyridine is formed instead(9g and 9h). Interestingly, atropisomers are obtained in these cases.This is because the plane containing the OCF₃ group is orthogonal to thepyridine plane, which prevents the free rotation of amide group (seeSupporting Information).^(1b, 3a-3d) Thirdly, the regioselectivityerodes as the reaction temperature increases (9d-f, 9o, 9u). Finally,substrates with the protected N-hydroxylamino-group at α-, γ-, orα′-position do not give the product of trifluoromethoxylation.Presumably, the formation of nitrenium ion is energetically disfavoredin these cases, because it involves placing the positive charge on theendocyclic nitrogen atom.²⁷ Products 9a-9y are shown in FIG. 2.

Methyl (5-bromo-6-methoxypyridin-3-yl)(hydroxy)carbamate (8a)

Under N₂ atmosphere, to a suspension of3-bromo-2-methoxy-5-nitropyridine (5.00 g, 21.5 mmol, 1.00 equiv) and 5%Rh/C (0.123 g, 0.30 mol % Rh) in THF (107 mL, 0.200 M) hydrazinemonohydrate (1.56 g, 25.8 mmol, 1.20 equiv) was added dropwise. Thereaction mixture was monitored via TLC using EtOAc:hexanes 1:1 (v/v) asan eluent until the disappearance of the starting3-bromo-2-methoxy-5-nitropyridine (R_(f)=0.90 (EtOAc:hexanes 1:1 (v/v))and the appearance of the hydroxylamine intermediate (R_(f)=0.61(EtOAc:hexanes 1:1 (v/v)). Subsequently, sodium bicarbonate (2.14 g,25.8 mmol, 1.20 equiv) was added to the reaction mixture followed by asolution of methyl chloroformate (2.42 g, 25.75 mmol, 1.20 equiv) in THF(6.58 mL, 0.200 M) via a syringe pump (at a rate of 10.0 mL/h). Afterthe addition was complete, the reaction mixture was filtered through ashort pad of celite and the celite was washed with EtOAc. The organiclayers were combined and concentrated in vacuo. The residue was purifiedby chromatography on silica gel, eluting with EtOAc:hexanes (3:7 to 1:1(v/v)), to afford the title compound as a slightly light yellow solid(3.82 g, 13.8 mmol, 64% yield). R_(f)=0.54 (EtOAc:hexanes 1:1 (v/v)).NMR Spectroscopy: ¹H NMR (500 MHz, (CD₃)₂SO, 25° C., δ): 10.60 (s, 1H)8.29 (d, J=2.44 Hz, 1H) 8.13 (d, J=2.44 Hz, 1H) 3.93 (s, 3H) 3.74 (s,3H). ¹³C NMR (125 MHz, (CD₃)₂SO, 25° C., δ): 156.97, 155.40, 138.89,135.74, 134. 47, 105.44, 55.01, 53.67. Mass Spectrometry: HRMS (ESI-TOF)(m/z): calcd for C₈H₁₀BrN₂O₄ ([M+H]⁺), 276.9818, found, 276.9821.

Methyl hydroxy (5-iodo-6-methoxypyridin-3-yl) carbamate (8b)

Under N₂ atmosphere, to a suspension of 3-iodo-2-methoxy-5-nitropyridine(0.500 g, 1.79 mmol, 1.00 equiv) and 5% Rh/C (10.3 mg, 0.30 mol % Rh) inTHF (8.93 mL, 0.200 M) hydrazine monohydrate (0.130 g, 2.14 mmol, 1.20equiv) was added dropwise. After the reaction mixture was stirred at 23°C. for 1 h, it was filtered through a short pad of celite andconcentrated in vacuo to afford the title compound as a slightly brownsolid (0.467 g, 1.76 mmol, 98% yield). The product was used directlywithout further purification. Under N₂ atmosphere, to a stirredsuspension of N-(5-iodo-6-methoxypyridin-3-yl)hydroxylamine (0.350 g,1.32 mmol, 1.00 equiv) and NaHCO₃ (0.131 g, 1.58 mmol, 1.20 equiv) inTHF (6.58 mL, 0.200 M) at 23° C. was slowly added a solution of methylchloroformate (0.148 g, 1.58 mmol, 1.20 equiv) in THF (6.58 mL, 0.200 M)via a syringe pump (at a rate of 10.0 mL/h). After the addition wascomplete, the reaction mixture was filtered through a short pad ofcelite and the celite was washed with EtOAc. The organic layers werecombined and concentrated in vacuo. The residue was purified bychromatography on silica gel, eluting with EtOAc:hexanes (1:1 to 1:0(v/v)), to afford the title compound as a slightly light brown solid(0.229 g, 0.710 mmol, 54% yield). R_(f)=0.63 (EtOAc:hexanes 1:0 (v/v)).NMR Spectroscopy: ¹H NMR (500 MHz, (CD₃)₂SO, 25° C., δ): 10.54 (br. s,1H) 8.26 (br. s, 2H) 3.89 (br. s, 3H) 3.73 (br. s, 3H). ¹³C NMR (125MHz, (CD₃)₂SO, 25° C., δ): 158.8, 154.9, 141.5, 139.4, 134.0, 79.1,54.8, 53.1. HRMS (ESI-TOF) (m/z): calcd for C₈H₁₀IN₂O₄ ([M+H]⁺),324.9680, found, 324.9682.

Methyl (6-chloro-4-methylpyridin-3-yl)(hydroxy)carbamate (8c)

Under N₂ atmosphere, hydrazine monohydrate (1.04 g, 20.9 mmol, 1.20equiv) was added dropwise to a suspension of2-chloro-4-methyl-5-nitropyridine (3.00 g, 17.4 mmol, 1.00 equiv) and 5%Rh/C (0.300 g, 0.838 mol % Rh) in THF (85.0 mL, 0.204 M) at 23° C. Thereaction mixture was stirred at 23° C. for 3 h and filtered through ashort pad of celite. The celite was washed with EtOAc. The organicsolutions were combined and concentrated in vacuo to afford the titlecompound as a white solid (2.70 g, 17.1 mmol, 98% yield). The productwas used directly without further purification. Under N₂ atmosphere, asolution of methyl chloroformate (0.623 g, 6.59 mmol, 1.10 equiv) in1,4-dioxane (10.0 mL, 0.660 M) was slowly added to a stirred suspensionof N-(6-chloro-4-methylpyridin-3-yl)hydroxylamine (0.950 g, 5.99 mmol,1.00 equiv) and NaHCO₃ (0.554 g, 6.59 mmol, 1.10 equiv) in 1,4-dioxane(40.0 mL, 0.150 M) at 23° C. After the reaction was complete (4 h), thereaction mixture was concentrated in vacuo. The residue was purified bychromatography on silica gel, eluting with hexanes:EtOAc (4:1 to 3:2(v/v)), to afford the title compound as a red solid (0.890 g, 4.11 mmol,69% yield). R_(f)=0.27 (hexanes/EtOAc 3:2 (v/v)). ¹H NMR (700 MHz,(CD₃)₂SO, 25° C., δ): 10.53 (s, 1H), 8.29 (s, 1H), 7.52 (s, 1H), 3.68(s, 3H), 2.23 (s, 3H). ¹³C NMR (175 MHz, (CD₃)₂SO, 25° C., δ): 155.6,148.8, 148.4, 147.9, 137.7, 125.6, 53.2, 16.8. Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₈H₁₀ClN₂O₃ ([M+H]⁺), 217.0374, found,217.0373.

Methyl (6-bromopyridin-3-yl)(hydroxy)carbamate (8d)

Under N₂ atmosphere, hydrazine monohydrate (0.888 g, 17.7 mmol, 1.20equiv) was added dropwise to a suspension of 2-bromo-5-nitropyridine(3.00 g, 14.8 mmol, 1.00 equiv) and 5% Rh/C (0.290 g, 0.952 mol % Rh) inTHF (75.0 mL, 0.197 M) at 23° C. After the reaction was complete (2.5h), the reaction mixture was filtered through a short pad of celite andthe celite was washed with EtOAc. The organic solutions were combinedand concentrated in vacuo to afford the title compound as a yellow solid(2.70 g, 14.3 mmol, 97% yield). The product was used directly withoutfurther purification. Under N₂ atmosphere, a solution of methylchloroformate (0.520 g, 5.50 mmol, 1.10 equiv) in 1,4-dioxane (10.0 mL,0.550 M) was added dropwise to a stirred suspension ofN-(6-bromopyridin-3-yl)hydroxylamine (0.940 g, 5.00 mmol, 1.00 equiv)and NaHCO₃ (0.462 g, 5.50 mmol, 1.10 equiv) in 1,4-dioxane (40.0 mL,0.125 M) at 23° C. After the reaction was complete (3 h), the reactionmixture was filtered through a short pad of celite and the celite waswashed with EtOAc. The combined organic layers were concentrated invacuo. The residue was purified by chromatography on silica gel, elutingwith hexanes:EtOAc (4:1 to 3:2 (v/v)), to afford the title compound as ayellow solid (0.870 g, 3.52 mmol, 71% yield). R_(f)=0.27 (hexanes/EtOAc3:2 (v/v)). ¹H NMR (500 MHz, (CD₃)₂SO, ° C., δ): 10.74 (s, 1H), 8.58 (d,J=2.7 Hz, 1H), 7.89 (dd, J=2.7, 3.8 Hz, 1H), 7.64 (d, J=3.8 Hz, 1H),3.78 (s, 3H). ¹³C NMR (125 MHz, (CD₃)₂SO, 25° C., δ): 154.4, 140.9,138.8, 134.9, 129.6, 127.5, 53.4. Mass Spectrometry: HRMS (ESI-TOF)(m/z): calcd for C₇H₈BrN₂O₃ ([M+H]⁺), 246.9713, found, 246.9712.

Methyl (6-fluoropyridin-3-yl)(hydroxy)carbamate (8e)

Under N₂ atmosphere, a suspension of 2-fluoro-5-nitropyridine (1.00 g,7.04 mmol, 1.00 equiv) and 5% Rh/C (80.8 mg, 0.60 mol % Rh) in THF (35.2mL, 0.200 M) was heated to 40° C. Hydrazine monohydrate (0.422 g, 8.44mmol, 1.20 equiv) was added all at once. The reaction mixture wasstirred at 40° C. for 30 min and then cooled down to 23° C. NaHCO₃(0.708 g, 8.44 mmol, 1.2 equiv) was added, followed by dropwise additionof methyl chloroformate (0.800 g, 8.44 mmol, 1.20 equiv) in THF (35.2mL, 0.240 M) at 23° C. After the reaction was complete (1 h), thereaction mixture was filtered through a short pad of celite, washed withEtOAc, and concentrated in vacuo. The residue was purified bychromatography on silica gel, eluting with hexanes:EtOAc (4:1 to 2:1(v/v)), to afford the title compound as a red solid (0.850 g, 4.57 mmol,65% yield). R_(f)=0.22 (hexanes:EtOAc 2:1 (v/v)). ¹H NMR (700 MHz,(CD₃)₂SO, 25° C., δ): 10.67 (s, 1H) 8.36 (d, J=1.29 Hz, 1H) 8.09-8.06(m, 1H) 7.21 (dd, J=8.82, 3.23 Hz, 1H) 3.76 (s, 3H). ¹³C NMR (175 MHz,(CD₃)₂SO, 25° C., δ): 159.3 (d, J=232.8 Hz), 154.8, 138.8 (d, J=15.8Hz), 137.3 (d, J=5.25 Hz), 133.8 (d, J=8.75 Hz), 109.2 (d, J=40.3 Hz),53.3. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −74.7 (s). Mass Spectrometry:HRMS (ESI-TOF) (m/z): calcd for C₇H₈FN₂O₃ ([M+H]⁺), 187.0513, found,187.0513.

Methyl (5-bromo-6-chloropyridin-3-yl)(hydroxy)carbamate (8f)

Under N₂ atmosphere, hydrazine monohydrate (0.506 g, 10.1 mmol, 1.20equiv) was added dropwise to a suspension of3-bromo-2-chloro-5-nitropyridine (2.00 g, 8.42 mmol, 1.00 equiv) andPt/C (0.200 g, 0.609 mol % Pt) in THF (75.0 mL, 0.112 M) at 23° C. Thereaction mixture was stirred at 23° C. for 3 h, filtered through a shortpad of celite, washed with EtOAc, and concentrated in vacuo. The residuewas dissolved in ether and filtered off. The filtrate was kept at −20°C. overnight and filtered again to remove the solid. The filtrate wasconcentrated in vacuo to afford the title compound as a yellow solid(1.22 g, 5.46 mmol, 65% yield). The product was used directly withoutfurther purification. Under N₂ atmosphere, a solution of methylchloroformate (0.256 g, 2.71 mmol, 1.10 equiv) in 1,4-dioxane (10.0 mL,0.271 M) was added dropwise to a stirred suspension ofN-(5-bromo-6-chloropyridin-3-yl)hydroxylamine (0.550 g, 2.46 mmol, 1.00equiv) and NaHCO₃ (0.227 g, 2.71 mmol, 1.10 equiv) in 1,4-dioxane (15.0mL, 0.164 M) at 23° C. The reaction mixture was stirred for 6 h andconcentrated in vacuo. The residue was purified by chromatography onsilica gel, eluting with hexanes:EtOAc (4:1 to 3:2 (v/v)), to afford thetitle compound as a yellow solid (0.55 g, 1.95 mmol, 80% yield).R_(f)=0.42 (hexanes/EtOAc 3:2 (v/v)). ¹H NMR (500 MHz, (CD₃)₂SO, 25° C.,δ): 10.89 (s, 1H), 8.63 (d, J=2.3 Hz, 1H), 8.33 (d, J=2.3 Hz, 1H), 3.80(s, 3H). ¹³C NMR (125 MHz, (CD₃)₂SO, 25° C., δ): 154.3, 143.0, 138.9,138.4, 131.7, 118.5, 53.6. Mass Spectrometry: HRMS (ESI-TOF) (m/z):calcd for C₇H₇BrClN₂O₃ ([M+H]⁺), 282.9301, found, 282.9302.

Methyl (2-chloropyridin-3-yl)(hydroxy)carbamate (8g)

Under N₂ atmosphere, hydrazine monohydrate (1.89 g, 37.8 mmol, 1.20equiv) was added dropwise to a suspension of 2-chloro-3-nitropyridine(5.00 g, 31.5 mmol, 1.00 equiv) and Rh/C (0.500 g, 0.771 mol % Rh) inTHF (150 mL, 0.210 M) at 23° C. The reaction mixture was stirred at 23°C. for 3 h, filtered through a short pad of celite, washed with EtOAc,and concentrated in vacuo to afford of the title compound as a red solid(4.50 g, 31.1 mmol, 98% yield). The product was used directly withoutfurther purification. Under N₂ atmosphere, a solution of methylchloroformate (0.140 g, 1.53 mmol, 1.10 equiv) in dioxane (7.00 mL,0.220 M) was slowly added via a syringe pump (at a rate of 10.0 mL/h) toa stirred suspension of N-(2-chloropyridin-3-yl)hydroxylamine (0.200 g,1.39 mmol, 1.00 equiv), NaHCO₃ (0.130 g, 1.53 mmol, 1.10 equiv) and DMAP(8.50 mg, 0.0700 mmol, 0.0500 equiv) in dioxane (7.00 mL, 0.200 M) at50° C. After the addition was complete, the reaction mixture was stirredat 50° C. for another 12 h and then filtered through a short pad ofcelite and the celite was washed with EtOAc. The organic layers werecombined and concentrated in vacuo. The residue was purified bychromatography on silica gel, eluting with hexanes:EtOAc (5:1 to 1:1(v/v)), to afford the title compound as a yellow gum (0.210 g, 1.04mmol, 75% yield). R_(f)=0.19 (hexanes/EtOAc 5:1 (v/v)). ¹H NMR (700 MHz,(CD₃)₂SO, 25° C., δ): 10.63 (s, 1H), 8.39 (dd, J=4.73, 1.72 Hz, 1H),7.96 (dd, J=7.74, 1.72 Hz, 1H), 7.52 (dd, J=7.74, 4.73 Hz, 1H), 3.69 (s,3H). ¹³C NMR (175 MHz, (CD₃)₂SO, 25° C., δ): 155.3, 148.9, 148.1, 137.9,136.6, 124.0, 53.2. Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd forC₇H₈ClN₂O₃ ([M+H]⁺), 203.0218, found, 203.0231.

N-(2,6-Dichloropyridin-3-yl)-N-hydroxyacetamide (8h)

Under N₂ atmosphere, a suspension of 2-fluoro-5-nitropyridine (1.00 g,7.04 mmol, 1.00 equiv) and 5% Rh/C (80.8 mg, 0.60 mol % Rh) in THF (35.2mL, 0.200 M) was heated to 40° C. Hydrazine monohydrate (0.422 g, 8.44mmol, 1.20 equiv) was added all at once. The reaction mixture wasstirred at 40° C. for 30 min and then cooled down to 23° C. NaHCO₃(0.708 g, 8.44 mmol, 1.2 equiv) was added, followed by dropwise additionof methyl chloroformate (0.800 g, 8.44 mmol, 1.20 equiv) in THF (35.2mL, 0.240 M) at 23° C. The reaction mixture was stirred at 23° C. for 1h and then filtered through a short pad of celite, washed with EtOAc,and concentrated in vacuo. The residue was purified by chromatography onsilica gel, eluting with hexanes:EtOAc (4:1 to 2:1 (v/v)), to afford thetitle compound as a red solid (0.850 g, 4.57 mmol, 65% yield).R_(f)=0.22 (hexanes:EtOAc 2:1 (v/v)). ¹H NMR (700 MHz, (CD₃)₂SO, 25° C.,δ): 10.95 (br. s., 1H), 8.01 (d, J=7.74 Hz, 1H), 7.67 (d, J=8.17 Hz,1H), 2.19 (br. s., 3H). ¹³C NMR (175 MHz, (CD₃)₂SO, 25° C., δ): 171.0,147.5, 146.9, 140.9, 135.9, 124.6, 20.8. Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₇H₇Cl₂N₂O₂ ([M+H]⁺), 220.9879, found,220.9878.

N-Hydroxy-N-(6-methoxy-4-methylpyridin-3-yl)acetamide (8i)

Under N₂ atmosphere, a suspension of 2-methoxy-4-methyl-5-nitropyridine(491 mg, 2.92 mmol, 1.00 equiv) and 5% Rh/C (33.6 mg, 0.60 mol % Rh) indioxane (14.6 mL, 0.200 M) was stirred at 40° C. Hydrazine monohydrate(146 mg, 3.50 mmol, 1.20 equiv) in dioxane (14.6 mL, 0.240 M) was addedvia a syringe pump (at a rate of 15.0 mL/h). The reaction mixture wasstirred at 40° C. for 1 h and then cooled down to 23° C. NaHCO₃ (290 mg,3.50 mmol, 1.2 equiv) was added, followed by dropwise addition of acetylchloride (270 mg, 3.50 mmol, 1.20 equiv) in THF (29.2 mL, 0.120 M) at23° C. The reaction mixture was stirred at 23° C. for 1 h and thenfiltered through a short pad of celite, washed with EtOAc, andconcentrated in vacuo. The residue was purified by chromatography onsilica gel, eluting with hexanes:EtOAc (4:1 to 1:1 (v/v)), to afford thetitle compound as a brown solid (450 mg, 2.29 mmol, 79% yield).R_(f)=0.08 (hexanes:EtOAc 4:1 (v/v)). ¹H NMR (700 MHz, (CD₃)₂SO, 90° C.,δ): 10.21 (br. s., 1H), 8.01 (s, 1H), 6.73 (s, 1H), 3.86 (s, 3H), 2.18(s, 3H), 2.08 (s, 3H). ¹³C NMR (175 MHz, (CD₃)₂SO, 25° C., δ): 170.9,162.9, 148.1, 145.7, 132.4, 110.9, 53.4, 20.8, 17.1. Mass Spectrometry:HRMS (ESI-TOF) (m/z): calcd for C₉H₁₃N₂O₃ ([M+H]⁺), 197.0921, found,197.0936.

N-Hydroxy-N-(6-methylpyridin-3-yl)acetamide (8j)

Under N₂ atmosphere, hydrazine monohydrate (0.870 g, 17.4 mmol, 1.20equiv) was added dropwise to a suspension of 2-methyl-5-nitropyridine(2.00 g, 14.5 mmol, 1.00 equiv) and Rh/C (0.120 g, 0.402 mol % Rh) inTHF (75.0 mL, 0.193 M) at 23° C. The reaction mixture was stirred at 23°C. for 2 h, filtered through a short pad of celite, washed with EtOAc,and concentrated in vacuo to afford the title compound as a yellow solid(1.63 g, 13.1 mmol, 91% yield). The product was used directly withoutfurther purification. Under N₂ atmosphere, a solution of acetyl chloride(0.300 g, 3.87 mmol, 1.20 equiv) in THF (16.00 mL, 0.240 M) was addeddropwise to a stirred suspension ofN-(6-methylpyridin-3-yl)hydroxylamine (S6) (0.400 g, 3.22 mmol, 1.00equiv) and NaHCO₃ (0.330 g, 3.87 mmol, 1.20 equiv) in THF (16.00 mL,0.200 M) at 23° C. The reaction mixture was stirred at 23° C. foranother 30 min and then filtered through a short pad of celite and thecelite was washed with EtOAc. The organic layers were combined andconcentrated in vacuo. The residue was purified by chromatography onsilica gel, eluting with EtOAc to afford the title compound as a lightyellow solid (0.176 g, 1.06 mmol, 33% yield). R_(f)=0.17 (EtOAc). ¹H NMR(700 MHz, (CD₃)₂SO, 25° C., δ): 10.77 (br. s, 1H), 8.72 (br. s, 1H),7.87 (dd, J=8.17, 2.15 Hz, 1H), 7.25 (d, J=8.60 Hz, 1H), 2.43 (s, 3H),2.21 (br. s, 3H). ¹³C NMR (175 MHz, (CD₃)₂SO, 25° C., δ): 170.4, 153.6,140.5, 136.0, 127.4, 122.6, 23.4, 22.1. Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₈H₁₁N₂O₂ ([M+H]⁺), 167.0815, found,167.0816.

Methyl (5-(2,4-difluorophenyl)-6-methoxypyridin-3-yl)(hydroxy) carbamate(8k)

Under N₂ atmosphere, to a suspension of3-(2,4-difluorophenyl)-2-methoxy-5-nitropyridine (0.300 g, 1.13 mmol,1.00 equiv) and 5% Rh/C (6.5 mg, 0.30 mol % Rh) in THF (11.3 mL, 0.100M) hydrazine monohydrate (0.083 g, 1.35 mmol, 1.20 equiv) was addeddropwise. The reaction mixture was stirred at 23° C. for 1 h andfiltered through a short pad of celite. The pad of celite was washedwith EtOAc. The combined organic solution was concentrated in vacuo toafford the title compound as a slightly light yellow solid (0.245 g,0.973 mmol, 86% yield). The product was used directly without furtherpurification. Under N₂ atmosphere, to a stirred suspension ofN-(5-(2,4-difluorophenyl)-6-methoxypyridin-3-yl)hydroxylamine (0.250 g,0.99 mmol, 1.00 equiv) and NaHCO₃ (0.099 g, 6.46 mmol, 1.20 equiv) inTHF (4.96 mL, 0.200 M) at 23° C. was slowly added a solution of methylchloroformate (0.112 g, 1.19 mmol, 1.20 equiv) in THF (4.96 mL, 0.200 M)via a syringe pump (at a rate of 10.0 mL/h). After the addition wascomplete, the reaction mixture was filtered through a short pad ofcelite and the celite was washed with EtOAc. The organic layers werecombined and concentrated in vacuo. The residue was purified bychromatography on silica gel, eluting with EtOAc:hexanes (1:2 to 1:1(v/v)), to afford the title compound as a slightly yellow solid (0.163g, 0.52 mmol, 52% yield). R_(f)=0.31 (EtOAc:hexanes 1:1 (v/v)). ¹H NMR(700 MHz, (CD₃)₂SO, 25° C., δ): 10.54 (s, 1H), 8.32 (s, 1H), 7.77 (s,1H), 7.49 (q, J=8.03 Hz, 1H), 7.35 (t, J=9.68 Hz, 1H), 7.18 (t, J=8.17Hz, 1H), 3.85 (s, 3H), 3.73 (s, 3H). ¹³C NMR (175 MHz, (CD₃)₂SO, 25° C.,δ): 162.2 (d, J=246.9 Hz), 159.5 (d, J=247.5 Hz), 157.7, 155.1, 139.9,133.7, 133.4, 132.9 (m), 119.9 (d, J=15.2 Hz), 116.9, 111.7 (dd, J=22.8Hz, J=5.3 Hz), 104.2 (t, J=26.3 Hz), 53.81, 53.1. ¹⁹F NMR (376 MHz,(CD₃)₂SO, 25° C., δ): −111.2 (m), −112.1 (m). Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₁₄H₁₃F₂N₂O₄ ([M+H]⁺), 311.0838, found,311.0841.

Methyl (6-(4-(tert-butyl)phenoxy)pyridin-3-yl)(hydroxy)carbamate (8l)

Under N₂ atmosphere, to a suspension of2-(4-(tert-butyl)phenoxy)-5-nitropyridine (0.600 g, 2.20 mmol, 1.00equiv) and 5% Rh/C (12.7 mg, 0.30 mol % Rh) in THF (11.0 mL, 0.200 M)hydrazine monohydrate (0.160 g, 2.64 mmol, 1.20 equiv) was addeddropwise. The reaction mixture was stirred at 23° C. for 1 h and thenfiltered through a short pad of celite. The celite was washed withEtOAc. The combined organic solution was concentrated in vacuo to affordthe title compound as an off-white solid (0.495 g, 1.92 mmol, 86%yield). The product was used directly without further purification.Under N₂ atmosphere, to a stirred suspension ofN-(6-(4-(tert-butyl)phenoxy)pyridin-3-yl)hydroxylamine (0.491 g, 0.990mmol, 1.00 equiv) and NaHCO₃ (0.099 g, 1.19 mmol, 1.20 equiv) in THF(4.96 mL, 0.100 M) at 23° C. was slowly added a solution of methylchloroformate (0.112 g, 1.19 mmol, 1.20 equiv) in THF (4.96 mL, 0.100 M)via a syringe pump (at a rate of 10.0 mL/h). After the addition wascomplete, the reaction mixture was filtered through a short pad ofcelite and the celite was washed with EtOAc. The organic layers werecombined and concentrated in vacuo. The residue was purified bychromatography on silica gel, eluting with EtOAc:hexanes (1:2 to 1:1(v/v)), to afford the title compound as a off-white solid (0.163 g, 0.52mmol, 52% yield). R_(f)=0.48 (EtOAc:hexanes 1:1 (v/v)). ¹H NMR (700 MHz,(CD₃)₂SO, 25° C., δ): 10.53 (s, 1H), 8.23 (d, J=2.58 Hz, 1H), 7.91 (dd,J=9.03, 2.58 Hz, 1H), 7.42 (d, J=8.60 Hz, 2H), 7.08-6.97 (m, 3H), 3.72(s, 3H), 1.30 (s, 9H). ¹³C NMR (175 MHz, (CD₃)₂SO, 25° C., δ): 160.0,155.0, 151.7, 146.8, 140.2, 134.8, 133.4, 126.4, 120.5, 111.0, 53.1,34.2, 31.3. Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd forC₁₇H₂₁N₂O₄ ([M+H]⁺), 317.1496, found, 317.1497.

Methyl (5-(5-formylfuran-2-yl)-6-methoxypyridin-3-yl)(hydroxy) carbamate(8m)

Methyl (5-bromo-6-methoxypyridin-3-yl)(hydroxy)carbamate (0.400 g, 1.44mmol, 1.00 equiv), (5-formylfuran-2-yl)boronic acid (0.283 g, 2.02 mmol,1.40 equiv), Na₂CO₃ (0.383 g, 3.61 mmol, 2.5 equiv), THF:H₂O 4:3 (8.42mL, 0.200 M), and palladium-tetrakis(triphenylphosphine) (0.0830 g,0.0700 mmol, 0.05 equiv) were degassed via three freeze-pump-thawcycles. The resulting mixture was heated at 60° C. overnight and thenallowed to cool to room temperature after which water was added. Themixture was then extracted with dichloromethane and the organic extractswas dried with MgSO₄, filtered and concentrated in vacuo. The residuewas purified by chromatography on silica gel, eluting with EtOAc:hexanes(3:8 to 1:1 (v/v)), to afford the pure cross-coupled product as aslightly light orange solid (0.070 g, 0.24 mmol, 16% yield). R_(f)=0.21(EtOAc:hexanes 4:6 (v/v)). ¹H NMR (700 MHz, (CD₃)₂SO, 25° C., δ): 10.65(s, 1H), 9.65 (s, 1H), 8.38 (d, J=2.58 Hz, 1H), 8.32 (d, J=2.58 Hz, 1H),7.68 (d, J=3.44 Hz, 1H), 7.28 (d, J=3.87 Hz, 1H), 4.05 (s, 3H), 3.76 (s,3H). ¹³C NMR (175 MHz, (CD₃)₂SO, 25° C., δ): 178.2, 156.4, 155.0, 152.4,151.6, 139.9, 133.8, 127.7, 125.2, 113.6, 111.4, 54.2, 53.2. MassSpectrometry: HRMS (ESI-TOF) (m/z): calcd for C₁₃H₁₃N₂O₆ ([M+H]⁺),294.0799, found, 294.0801.

N-(6-(1H-Pyrazol-1-yl)pyridin-3-yl)-N-hydroxyacetamide (8n)

Under N₂ atmosphere, a solution of 2-fluoro-5-nitropyridine (0.71 g,5.00 mmol, 1.00 equiv) was added to a mixture of 1H-pyrazole (0.51 g,7.50 mmol, 1.50 equiv) and Cs₂CO₃ (2.44 g, 7.50 mmol, 1.50 equiv) in DMF(25.0 mL, 0.300 M) and the reaction mixture was stirred at 23° C. for 20h. The reaction mixture was poured to LiCl solution (100 mL), extractedwith EtOAc. The combined organic layers was dried (MgSO₄), filtered andconcentrated in vacuo. The residue was recrystalized from hexanes/EtOAc,to afford the title compound as a yellow solid (0.910 g, 4.78 mmol, 96%yield). R_(f)=0.77 (hexanes:EtOAc 5:1 (v/v)). ¹H NMR (700 MHz, (CD₃)₂SO,25° C., δ): 9.29 (br. s., 1H), 8.75 (d, J=8.17 Hz, 1H), 8.73-8.71 (m,1H), 8.12 (d, J=9.04 Hz, 1H), 7.99-7.98 (m, 1H), 6.72-6.70 (m, 1H). ¹³CNMR (175 MHz, (CD₃)₂SO, 25° C., δ): 153.7, 145.0, 144.4, 142.3, 135.3,128.5, 112.2, 110.0. Under N₂ atmosphere, a suspension of5-nitro-2-(1H-pyrazol-1-yl)pyridine 200 mg, 1.05 mmol, 1.00 equiv) and5% Rh/C (12.6 mg, 0.60 mol % Rh) in THF (10.5 mL, 0.100 M) was stirredat 23° C. Hydrazine monohydrate (63.1 mg, 1.26 mmol, 1.20 equiv) wasadded dropwise. The reaction mixture was stirred at 23° C. for 20 min.NaHCO₃ (106 mg, 1.26 mmol, 1.20 equiv) was added, followed by dropwiseaddition of acetyl chloride (98.9 mg, 1.26 mmol, 1.20 equiv) in THF(10.5 mL, 0.120 M) at 23° C. The reaction mixture was stirred at 23° C.for 30 min and then filtered through a short pad of celite. The celitewas washed with EtOAc. The combined organic solution was concentrated invacuo. The residue was recrystalized from hexanes/EtOAc, to afford thetitle compound as a yellow solid (200 mg, 0.917 mmol, 87% yield).R_(f)=0.26 (hexanes:EtOAc 1:1 (v/v)). ¹H NMR (700 MHz, (CD₃)₂SO, 25° C.,δ): 10.95 (br. s., 1H), 8.77 (br. s., 1H), 8.59 (d, J=2.15 Hz, 1H), 8.22(dd, J=9.03, 2.58 Hz, 1H), 7.95 (d, J=9.03 Hz, 1H), 7.82 (s, 1H),6.60-6.56 (m, 1H), 2.27 (s, 3H). ¹³C NMR (175 MHz, (CD₃)₂SO, 25° C., δ):170.6, 146.9, 142.1, 139.1, 136.7, 130.1, 126.9, 111.7, 108.2, 22.2.Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₁₀H₁₁N₄O₂ ([M+H]⁺),219.0877, found, 219.0877.

Methyl (6-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)(hydroxy)carbamate (8o)

Under N₂ atmosphere, to a suspension of5-nitro-2-(1H-1,2,4-triazol-1-yl)pyridine (0.500 g, 2.26 mmol, 1.00equiv) and 5% Rh/C (15.0 mg, 0.30 mol % Rh) in THF (13.0 mL, 0.200 M)hydrazine monohydrate (0.190 g, 3.14 mmol, 1.20 equiv) was addeddropwise. The reaction mixture was stirred at 23° C. for 1 h. Thereaction mixture was filtered through a short pad of celite, washed withEtOAc, and concentrated in vacuo to afford the title compound as aslightly light yellow (0.691 g, 2.38 mmol, 91% yield). The product wasused directly without further purification. R_(f)=0.36 (EtOAc:hexanes1:0 (v/v)). NMR Spectroscopy: ¹H NMR (700 MHz, (CD₃)₂SO, 25° C., δ):9.20 (s, 1H), 8.80 (s, 1H), 8.73 (d, J=2.15 Hz, 1H), 8.22 (s, 1H), 8.05(d, J=2.58 Hz, 1H), 7.71 (d, J=9.03 Hz, 1H), 7.45 (dd, J=8.82, 2.80 Hz,1H). ¹³C NMR (175 MHz, (CD₃)₂SO, 25° C., δ): 152.3, 147.9, 141.7, 141.0,132.8, 123.0, 113.3. Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd forC₇H₈N₅O ([M+H]⁺), 178.0723, found, 178.0723. Under N₂ atmosphere, to astirred suspension ofN-(6-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)hydroxylamine (0.150 g, 0.85mmol, 1.00 equiv) and NaHCO₃ (0.084 g, 1.02 mmol, 1.20 equiv) in THF(4.23 mL, 0.100 M) at 23° C. was slowly added a solution of methylchloroformate (0.095 g, 1.02 mmol, 1.20 equiv) in THF (4.23 mL, 0.100 M)via a syringe pump (at a rate of 10.0 mL/h). After the addition wascomplete, a white solid precipitated from the reaction mixture. Thereaction mixture was then filtered through and the solid was washed withwater to afford the title compound as a white solid (0.081 g, 0.34 mmol,41% yield). R_(f)=0.08 (MeOH:EtOAc 1:9 (v/v)). NMR Spectroscopy: ¹H NMR(700 MHz, (CD₃)₂SO, 25° C., δ): 10.80 (s, 1H), 9.33 (s, 1H), 8.72 (d,J=2.58 Hz, 1H), 8.29 (s, 1H), 8.19-8.17 (m, 1H), 7.89 (d, J=9.03 Hz,1H), 3.80 (s, 3H). ¹³C NMR (175 MHz, (CD₃)₂SO, 25° C., δ): 154.6, 152.9,144.6, 141.8, 139.2, 138.5, 130.2, 112.9, 53.4. Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₉H₉N₅O₃Na ([M+Na]⁺), 258.0598, found,258.0598.

N-(6-(1H-Benzo[d] imidazol-1-yl)pyridin-3-yl)-N-hydroxyacetamide (8p)

Under N₂ atmosphere, a solution of 2-fluoro-5-nitropyridine (1.32 g,9.31 mmol, 1.10 equiv) in DMF (20.0 mL, 0.466 M) was added to a mixtureof 1H-benzo[d]imidazole (1.00 g, 8.46 mmol, 1.00 equiv) and Cs₂CO₃ (2.76g, 8.46 mmol, 1.50 equiv) in DMF (22.3 mL, 0.379 M) at 23° C. Theresulting mixture was stirred at 23° C. for 7 h. The reaction mixturewas poured to LiCl solution (100 mL), extracted with EtOAc. The combinedorganic layers was dried (MgSO₄), filtered and concentrated in vacuo.The residue was recrystalized from hexanes/EtOAc, to afford the titlecompound as a yellow solid (1.38 g, 5.75 mmol, 68% yield). R_(f)=0.29(hexanes:EtOAc 1:1 (v/v)). NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃, 25°C., δ): 9.46 (d, J=2.58 Hz, 1H), 8.75-8.72 (m, 1H), 8.72-8.68 (m, 1H),8.22 (d, J=8.17 Hz, 1H), 7.90 (d, J=7.74 Hz, 1H), 7.79 (dd, J=8.82, 1.94Hz, 1H), 7.49-7.46 (m, 1H), 7.45-7.42 (m, 1H). ¹³C NMR (175 MHz, CDCl₃,25° C., δ): 153.6, 145.9, 144.9, 141.9, 141.1, 134.7, 131.8, 125.5,124.7, 121.3, 113.7, 112.8. Mass Spectrometry: HRMS (ESI-TOF) (m/z):calcd for C₁₂H₉N₄O₂ ([M+H]⁺), 241.0720, found, 241.0724.

Under N₂ atmosphere, a suspension of1-(5-nitropyridin-2-yl)-1H-benzo[d]imidazole (600 mg, 2.50 mmol, 1.00equiv) and 5% Rh/C (28.7 mg, 0.60 mol % Rh) in THF (25.0 mL, 0.100 M)was stirred at 23° C. Hydrazine monohydrate (150 mg, 3.00 mmol, 1.20equiv) was added dropwise. The reaction mixture was stirred at 23° C.for 20 min. NaHCO₃ (252 mg, 3.00 mmol, 1.20 equiv) was added, followedby dropwise addition of a solution of acetyl chloride (236 mg, 3.00mmol, 1.20 equiv) in THF (25.0 mL, 0.120 M). The reaction mixture wasstirred at 23° C. for 30 min and then filtered through a short pad ofcelite. The celite was washed with EtOAc. The combined organic solutionwas concentrated in vacuo. The residue was recrystalized fromhexanes/EtOAc, to afford the title compound as a yellow solid (650 mg,2.42 mmol, 97% yield). R_(f)=0.15 (EtOAc). NMR Spectroscopy: ¹H NMR (700MHz, (CD₃)₂SO, 25° C., δ): 11.01 (br. s., 1H), 8.92 (s, 2H), 8.28 (dd,J=9.03, 2.58 Hz, 1H), 8.25 (d, J=7.74 Hz, 1H), 7.97 (d, J=9.03 Hz, 1H),7.77 (d, J=7.74 Hz, 1H), 7.40-7.36 (m, 1H), 7.35-7.32 (m, 1H), 2.29 (s,3H). ¹³C NMR (175 MHz, (CD₃)₂SO, 25° C., δ): 170.8, 145.5, 144.1, 142.2,139.7, 136.6, 131.9, 130.0, 123.9, 123.0, 119.9, 114.4, 113.7, 22.2.Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₁₄H₁₃N₄O₂ ([M+H]⁺),269.1033, found, 269.1037.

N-(6-(1H-Benzo[d] [1,2,3]triazol-1-yl)pyridin-3-yl)-N-hydroxyacetamide(8q)

Under N₂ atmosphere, to a mixture of 1H-benzo[d] [1,2,3]triazole (0.890g, 7.50 mmol, 1.50 equiv) and Cs₂CO₃ (2.44 g, 7.50 mmol, 1.50 equiv) inDMF (25.0 mL, 0.300 M) was added 2-fluoro-5-nitropyridine (0.71 g, 5.00mmol, 1.00 equiv) and the reaction mixture was stirred at 23° C. for 20h. The reaction mixture was poured to LiCl solution (100 mL), extractedwith EtOAc. The combined organic layers was dried (MgSO₄), filtered andconcentrated in vacuo. The residue was recrystalized from hexanes/EtOAc,to afford the title compound as a yellow solid (0.870 g, 3.61 mmol, 72%yield). R_(f)=0.54 (hexanes:EtOAc 5:1 (v/v)). ¹H NMR (700 MHz, (CD₃)₂SO,25° C., δ): 9.52 (br. s., 1H), 8.90 (d, J=9.03 Hz, 1H), 8.65 (d, J=8.17Hz, 1H), 8.51 (d, J=9.04 Hz, 1H), 8.28 (d, J=8.17 Hz, 1H), 7.82 (t,J=7.53 Hz, 1H), 7.63 (t, J=7.53 Hz, 1H). ¹³C NMR (175 MHz, (CD₃)₂SO, 25°C., δ): 153.8, 146.3, 145.1, 142.7, 135.4, 130.9, 130.2, 126.1, 120.1,114.7, 114.3. Under N₂ atmosphere, a suspension of1-(5-nitropyridin-2-yl)-1H-benzo[d] [1,2,3]triazole (S15) (253 mg, 1.05mmol, 1.00 equiv) and 5% Rh/C (12.6 mg, 0.60 mol % Rh) in THF (21.0 mL,0.0500 M) was stirred at 23° C. Hydrazine monohydrate (63.1 mg, 1.26mmol, 1.20 equiv) was added dropwise. The reaction mixture was stirredat 23° C. for 20 min. NaHCO₃ (106 mg, 1.26 mmol, 1.20 equiv) was added,followed by dropwise addition of a solution of acetyl chloride (98.9 mg,1.26 mmol, 1.20 equiv) in THF (10.5 mL, 0.120 M). The reaction mixturewas stirred at 23° C. for 30 min and then filtered through a short padof celite. The celite was washed with EtOAc. The combined organicsolution was concentrated in vacuo. The residue was recrystalized fromhexanes/EtOAc, to afford the title compound as a yellow solid (281 mg,1.04 mmol, 99% yield). R_(f)=0.34 (hexanes:EtOAc 1:1 (v/v)). NMRSpectroscopy: ¹H NMR (700 MHz, (CD₃)₂SO, 25° C., δ): 11.07 (s, 1H), 9.02(d, J=2.58 Hz, 1H), 8.56 (d, J=8.17 Hz, 1H), 8.39 (dd, J=9.03, 2.58 Hz,1H), 8.28 (d, J=9.03 Hz, 1H), 8.22-8.19 (m, 1H), 7.72 (td, J=7.64, 1.08Hz, 1H), 7.55 (ddd, J=8.07, 6.99, 0.86 Hz, 1H), 2.31 (s, 3H). ¹³C NMR(175 MHz, (CD₃)₂SO, 25° C., δ): 171.2, 146.4, 146.0, 139.0, 137.5,130.8, 130.0, 129.2, 125.3, 119.6, 114.3, 114.2, 22.3. MassSpectrometry: HRMS (ESI-TOF) (m/z): calcd for C₁₃H₁₂N₅O₂ ([M+H]⁺),270.0986, found, 270.0986.

N-(6-(5-Fluoro-1H-indol-1-yl)pyridin-3-yl)-N-hydroxyacetamide (8r)

Under N₂ atmosphere, 5-fluoro-1H-indole (1.14 g, 8.45 mmol, 1.20 equiv)was dissolved in DMF (35.2 mL, 0.240 M) and stirred at 0° C. NaH (0.338g, 8.45 mmol, 1.20 equiv, 60% dispersion in mineral oil) was added inportionwise. After 30 min, 2-fluoro-5-nitropyridine (1.00 g, 7.04 mmol.1.00 equiv) was added and then the reaction mixture was slowly warmed upto 60° C. and stirred at 60° C. for 16 h. The reaction mixture waspoured to a solution of LiCl (100 mL), extracted with EtOAc, and washedwith brine. The combined organic layers was dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by chromatography onsilica gel, eluting with hexanes:EtOAc (10:1 to 5:1 (v/v)), to affordthe title compound as a yellow solid (1.63 g, 6.34 mmol, 90% yield).R_(f)=0.20 (hexanes:EtOAc 5:1 (v/v)). ¹H NMR (700 MHz, CDCl₃, 25° C.,δ): 9.39 (d, J=2.15 Hz, 1H), 8.58 (dd, J=9.03, 2.58 Hz, 1H), 8.51 (dd,J=9.25, 4.52 Hz, 1H), 7.76 (d, J=3.87 Hz, 1H), 7.54 (d, J=9.04 Hz, 1H),7.30 (dd, J=9.03, 2.58 Hz, 1H), 7.11 (td, J=9.03, 2.58 Hz, 1H), 6.78 (d,J=3.01 Hz, 1H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 159.5 (d, J=238.8Hz), 155.8, 145.6 (d, J=3.50 Hz), 140.4, 134.0, 132.1 (J=9.94 Hz),126.5, 116.4 (d, J=9.00 Hz), 112.5 (d, J=24.7 Hz), 112.0, 108.9 (d,J=3.76 Hz), 106.8 (d, J=23.6 Hz). ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ):−121.5.0 (m). Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd forC₁₃H₉FN₃O₂ ([M+H]⁺), 258.0673, found, 258.0675.

Under N₂ atmosphere, a suspension of5-fluoro-1-(5-nitropyridin-2-yl)-1H-indole (0.500 g, 1.94 mmol, 1.00equiv) and 5% Rh/C (21.8 mg, 0.60 mol % Rh) in THF (20.0 mL, 0.100 M)was stirred at 23° C. Hydrazine monohydrate (117 mg, 2.33 mmol, 1.20equiv) was added dropwise. The reaction mixture was stirred at 23° C.for 20 min. NaHCO₃ (196 mg, 2.33 mmol, 1.20 equiv) was added, followedby dropwise addition of a solution of acetyl chloride (183 mg, 2.33mmol, 1.20 equiv) in THF (20 mL, 0.120 M). The reaction mixture wasstirred at 23° C. for 30 min and then filtered through a short pad ofcelite. The celite was washed with EtOAc. The combined organic solutionwas concentrated in vacuo. The residue was purified by chromatography onsilica gel, eluting with hexanes:EtOAc (2:1 to 1:1 (v/v)), to afford thetitle compound as a yellow solid (0.490 g, 1.72 mmol, 89% yield).R_(f)=0.14 (hexanes:EtOAc 1:1 (v/v)). NMR Spectroscopy: ¹H NMR (700 MHz,(CD₃)₂SO, ° C., δ): 10.95 (br. s., 1H), 8.84 (br. s., 1H), 8.39 (dd,J=8.82, 4.52 Hz, 1H), 8.23-8.17 (m, 1H), 8.09 (d, J=3.44 Hz, 1H), 7.79(d, J=8.60 Hz, 1H), 7.43 (dd, J=9.25, 2.37 Hz, 1H), 7.10 (td, J=9.14,2.37 Hz, 1H), 6.75 (d, J=3.01 Hz, 1H), 2.27 (br. s., 3H), ¹³C NMR (175MHz, (CD₃)₂SO, 25° C., δ): 170.6, 157.8 (d, J=233.2 Hz), 148.0, 139.4,135.4, 131.3, 130.6 (d, J=10.1 Hz), 130.2, 128.2, 115.2 (d, J=9.14 Hz),113.6, 110.8 (d, J=25.2 Hz), 105.6 (d, J=23.3 Hz), 105.2 (d, J=3.38 Hz),22.1. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −123.6 (m). MassSpectrometry: HRMS (ESI-TOF) (m/z): calcd for C₁₅H₁₃FN₃O₂ ([M+H]⁺),286.0986, found, 286.0989.

N-(6-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-3-yl)-N-hydroxyacetamide (8s)

Under N₂ atmosphere, 5-bromo-1H-pyrrolo[2,3-b]pyridine (1.66 g, 8.45mmol, 1.20 equiv) was dissolved in DMF (35.2 mL, 0.240 M) and stirred at0° C. NaH (0.338 g, 8.45 mmol, 1.20 equiv, 60% dispersion in mineraloil) was added in portionwise. After 30 min, 2-fluoro-5-nitropyridine(1.00 g, 7.04 mmol. 1.00 equiv) was added and then the reaction mixturewas slowly warmed up to 60° C. and stirred at 60° C. for 16 h. Thereaction mixture was poured to a solution of LiCl (100 mL), extractedwith EtOAc. The combined organic layers washed with brine, dried(MgSO₄), filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel, eluting with hexanes:EtOAc (20:1 to 10:1(v/v)), to afford the title compound as a yellow solid (1.26 g, 3.94mmol, 56% yield). R_(f)=0.69 (hexanes:EtOAc 5:1 (v/v)). NMRSpectroscopy: ¹H NMR (500 MHz, CDCl₃, 25° C., δ): 9.31 (d, J=2.58 Hz,1H), 9.30 (d, J=9.04 Hz, 1H), 8.64 (d, J=2.58 Hz, 1H), 8.62 (d, J=2.58Hz, 1H), 8.49 (d, J=4.30 Hz, 1H), 8.46 (d, J=2.15 Hz, 1H), 8.10 (d,J=2.15 Hz, 1H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 153.8, 146.4,144.9, 144.3, 141.1, 134.0, 131.9, 127.8, 125.8, 114.6, 114.4, 104.5.Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₁₂H₈BrN₄O₂ ([M+H]⁺),318.9825, found, 318.9826. Under N₂ atmosphere, a suspension of5-bromo-1-(5-nitropyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine (350 mg, 1.10mmol, 1.00 equiv) and 5% Rh/C (12.6 mg, 0.60 mol % Rh) in THF (11.0 mL,0.100 M) was stirred at 23° C. Hydrazine monohydrate (65.9 mg, 1.32mmol, 1.20 equiv) was added dropwise. The reaction mixture was stirredat 23° C. for 20 min. NaHCO₃ (111 mg, 1.32 mmol, 1.2 equiv) was added,followed by dropwise addition of a solution of acetyl chloride (104 mg,1.32 mmol, 1.20 equiv) in THF (11.0 mL, 0.120 M). The reaction mixturewas stirred at 23° C. for 30 min and then filtered through a short padof celite. The celite was washed with EtOAc. The combined organicsolution was concentrated in vacuo. The residue was purified bychromatography on silica gel, eluting with hexanes:EtOAc (5:1 to 1:1(v/v)), to afford the title compound as a yellow solid (330 mg, 0.950mmol, 86% yield). R_(f)=0.17 (hexanes:EtOAc 1:1 (v/v)). ¹H NMR (700 MHz,(CD₃)₂SO, 25° C., δ): 10.94 (br. s., 1H), 8.83 (br. s., 1H), 8.71 (d,J=8.60 Hz, 1H), 8.46 (br. s., 1H), 8.39 (d, J=3.44 Hz, 1H), 8.36 (br.s., 1H), 8.24 (d, J=9.03 Hz, 1H), 6.74 (d, J=3.44 Hz, 1H), 2.27 (br. s.,3H). ¹³C NMR (175 MHz, (CD₃)₂SO, 25° C., δ): 170.6, 145.5, 145.0, 143.3,139.6, 136.0, 131.6, 129.6, 128.1, 124.4, 114.7, 112.7, 102.4, 22.2.Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₁₄H₁₂BrN₄O₂([M+H]⁺), 347.0138, found, 347.0142.

N-Hydroxy-N-(6-(2-(thiazol-4-yl)-1H-benzo[d]imidazol-1-yl)pyridin-3-yl)acetamide (8t)

Under N₂ atmosphere, a solution of 2-fluoro-5-nitropyridine (0.710 g,5.00 mmol, 1.00 equiv) in DMF (5 mL, 1.00 M) was added to a mixture of4-(1H-benzo[d]imidazol-2-yl)thiazole (1.51 g, 7.50 mmol, 1.50 equiv) andCs₂CO₃ (2.44 g, 7.50 mmol, 1.50 equiv) in DMF (20.0 mL, 0.372 M) at 23°C. The resulting mixture was stirred at 23° C. for 12 h. The reactionmixture was poured to LiCl solution (100 mL), extracted with EtOAc. Thecombined organic layers was dried (MgSO₄), filtered and concentrated invacuo. The residue was purified by chromatography on silica gel, elutingwith hexanes:EtOAc (2:1 to 1:1 (v/v)), to afford the title compound as ayellow solid (2.30 g, 7.11 mmol, 95% yield). R_(f)=0.34 (hexanes:EtOAc1:1 (v/v)). NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃, 25° C., δ): 9.41(d, J=2.15 Hz, 1H), 8.63 (d, J=2.15 Hz, 1H), 8.60-8.56 (m, 1H), 8.28 (d,J=2.15 Hz, 1H), 7.87 (d, J=7.74 Hz, 1H), 7.55 (d, J=7.74 Hz, 1H),7.44-7.38 (m, 2H), 7.38-7.34 (m, 1H). ¹³C NMR (175 MHz, CDCl₃, 25° C.,δ): 154.8, 153.1, 146.6, 146.4, 145.2, 143.1, 143.0, 135.3, 133.4,125.0, 124.4, 121.9, 121.5, 120.4, 111.3. Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₁₅H₁₀N₅O₂S ([M+H]⁺), 324.0550, found,324.0555. Under N₂ atmosphere, a suspension of4-(1-(5-nitropyridin-2-yl)-1H-benzo[d]imidazol-2-yl)thiazole (323 mg,1.00 mmol, 1.00 equiv) and 5% Rh/C (11.5 mg, 0.60 mol % Rh) in THF (10.0mL, 0.100 M) was stirred at 23° C. Hydrazine monohydrate (60.1 mg, 1.20mmol, 1.20 equiv) was added dropwise. The reaction mixture was stirredat 23° C. for 20 min. NaHCO₃ (101 mg, 1.20 mmol, 1.20 equiv) was added,followed by dropwise addition of acetyl chloride (94.2 mg, 1.20 mmol,1.20 equiv) in THF (10 mL, 0.120 M). The reaction mixture was stirred at23° C. for 30 min and then filtered through a short pad of celite. Thecelite was washed with EtOAc. The combined organic solution wasconcentrated in vacuo. The residue was recrystalized from hexanes/EtOAc,to afford the title compound as a yellow solid (303 mg, 0.862 mmol, 86%yield). R_(f)=0.14 (hexanes:EtOAc 1:1 (v/v)). NMR Spectroscopy: ¹H NMR(700 MHz, (CD₃)₂SO, 25° C., δ): 11.04 (s, 1H), 9.01 (d, J=1.72 Hz, 1H),8.91 (br. s., 1H), 8.44 (d, J=1.72 Hz, 1H), 8.26 (dd, J=8.60, 2.58 Hz,1H), 7.80 (d, J=8.17 Hz, 1H), 7.51 (d, J=8.60 Hz, 1H), 7.38-7.33 (m,2H), 7.32-7.29 (m, 1H), 2.31 (s, 3H). ¹³C NMR (175 MHz, (CD₃)₂SO, 25°C., δ): 171.0, 154.7, 146.6, 146.1, 145.1, 142.3, 139.4, 138.0, 135.8,128.6, 123.8, 123.2, 122.6, 121.5, 119.4, 111.1, 22.4. MassSpectrometry: HRMS (ESI-TOF) (m/z): calcd for C₁₇H₁₄N₅O₂S ([M+H]⁺),352.0863, found, 352.0869.

N-(6-(2,6-Dichloro-9H-purin-9-yl)pyridin-3-yl)-N-hydroxyacetamide (8u)

Under N₂ atmosphere, a solution of 2-fluoro-5-nitropyridine (0.78 g,5.50 mmol, 1.10 equiv) in DMF (5 mL, 1.1 M) was added to a mixture of2,6-dichloro-9H-purine (0.950 g, 5.00 mmol, 1.00 equiv) and Cs₂CO₃ (1.63g, 5.00 mmol, 1.00 equiv) in DMF (20 mL, 0.25 M) at 23° C. The reactionmixture was stirred at 23° C. for 12 h, poured to LiCl solution (100mL), extracted with EtOAc. The combined organic layers was dried(MgSO₄), filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel, eluting with hexanes:EtOAc (10:1 to 4:1(v/v)), to afford the title compound as a yellow solid (0.500 g, 1.61mmol, 32% yield). R_(f)=0.50 (hexanes:EtOAc 4:1 (v/v)). NMRSpectroscopy: ¹H NMR (500 MHz, CDCl₃, 25° C., δ): 9.40 (d, J=2.44 Hz,1H), 9.30 (s, 1H), 8.95 (d, J=8.85 Hz, 1H), 8.81 (dd, J=9.00, 2.59 Hz,1H). ¹³C NMR (125 MHz, CDCl₃, 25° C., δ): 154.4, 153.3, 152.0, 150.7,145.2, 143.8, 143.3, 135.4, 132.8, 115.0. Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₁₀H₅Cl₂N₆O₂ ([M+H]⁺), 310.9846, found,310.9848. Under N₂ atmosphere, a suspension of2,6-dichloro-9-(5-nitropyridin-2-yl)-9H-purine (270 mg, 0.870 mmol, 1.00equiv) and 5% Rh/C (10.0 mg, 0.60 mol % Rh) in THF (8.7 mL, 0.100 M) wasstirred at 23° C. Hydrazine monohydrate (52.0 mg, 1.04 mmol, 1.20 equiv)was added dropwise. The reaction mixture was stirred at 23° C. for 20min. NaHCO₃ (87.4 g, 1.04 mmol, 1.2 equiv) was added, followed bydropwise addition of a solution of acetyl chloride (81.6 mg, 1.04 mmol,1.20 equiv) in THF (8.7 mL, 0.120 M). The reaction mixture was stirredat 23° C. for 30 min and then filtered through a short pad of celite.The celite was washed with EtOAc. The combined organic solution wasconcentrated in vacuo. The residue was purified by chromatography onsilica gel, eluting with hexanes:EtOAc (1:1 to EtOAc (v/v)), to affordthe title compound as a yellow solid (110 mg, 0.324 mmol, 37% yield).R_(f)=0.13 (EtOAc). NMR Spectroscopy: ¹H NMR (500 MHz, (CD₃)₂SO, 25° C.,δ): 11.07 (br. s., 1H), 9.34 (s, 1H), 8.95 (d, J=2.44 Hz, 1H), 8.39 (dd,J=9.00, 2.59 Hz, 1H), 8.28 (d, J=8.85 Hz, 1H), 2.29 (s, 3H). ¹³C NMR(125 MHz, (CD₃)₂SO, 25° C., δ): 171.0, 152.1, 151.7, 150.3, 145.7,142.2, 139.5, 138.1, 131.8, 129.7, 115.7, 22.3. Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₁₂H₈C₁₃N₆O₂ ([M+H]⁺), 339.0159, found,339.0172.

Ethyl(E)-3-(4-fluoro-3-(5-(hydroxy(methoxycarbonyl)amino)-2-methoxypyridin-3-yl)phenyl)acrylate(8v)

Methyl (5-bromo-6-methoxypyridin-3-yl)(hydroxy)carbamate (1a) (0.300 g,1.08 mmol, 1.00 equiv),(E)-(5-(3-ethoxy-3-oxoprop-1-en-1-yl)-2-fluorophenyl)boronic acid (0.361g, 1.52 mmol, 1.40 equiv), Na₂CO₃ (0.287 g, 2.71 mmol, 2.5 equiv), andpalladium-tetrakis(triphenylphosphine) (0.062 g, 0.05 mmol, 0.05 equiv)in THF:H₂O 4:3 (6.32 mL, 0.200 M), were degassed via threefreeze-pump-thaw cycles. The resulting mixture was heated at 60° C.overnight and then allowed to cool to room temperature after which waterwas added (twice the volume of THF:H₂O 4:3 used). The mixture was thenextracted with dichloromethane (twice the volume of THF:H₂O 4:3 used)and the organic extracts was dried with MgSO₄, filtered and concentratedin vacuo. The residue was purified by chromatography on silica gel,eluting with EtOAc:hexanes (3:8 to 1:1 (v/v)), to afford the purecross-coupled product as a yellow solid (0.198 g, 0.51 mmol, 47% yield).R_(r)=0.36 (EtOAc:hexanes 1:1 (v/v)). NMR Spectroscopy: ¹H NMR (700 MHz,(CD₃)₂SO, 25° C., δ): 10.55 (s, 1H), 8.33 (d, J=2.58 Hz, 1H), 7.90-7.79(m, 3H), 7.68 (d, J=15.92 Hz, 1H), 7.35 (t, J=9.03 Hz, 1H), 6.67 (d,J=16.35 Hz, 1H), 4.18 (q, J=7.17 Hz, 2H), 3.86 (s, 3H), 3.73 (s, 3H),1.25 (t, J=7.10 Hz, 3H). ¹³C NMR (175 MHz, (CD₃)₂SO, 25° C., δ): 166.2,160.4 (d, J=250.2 Hz), 157.7, 155.2, 143.0, 140.1, 133.9, 133.4, 131.9(d, J=3.5 Hz), 130.8 (d, J=3.5 Hz), 130.3 (d, J=8.6 Hz), 124.1 (d,J=16.2 Hz), 118.6, 117.3, 116.3 (d, J=22.7 Hz), 60.1, 53.8, 53.1, 14.2.¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −111.3 (m).

Methyl4-((4-(5-(hydroxy(methoxycarbonyl)amino)-2-methoxypyridin-3-yl)phenyl)ethynyl)benzoate(8w)

Methyl (5-bromo-6-methoxypyridin-3-yl)(hydroxy)carbamate (1a) (0.300 g,1.08 mmol, 1.00 equiv), methyl4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethynyl)benzoate(0.152 g, 1.52 mmol, 1.40 equiv), Na₂CO₃ (0.287 g, 2.71 mmol, 2.5equiv), THF:H₂O 4:3 (6.32 mL, 0.200 M), andpalladium-tetrakis(triphenylphosphine) (0.062 g, 0.05 mmol, 0.05 equiv)were degassed via three freeze-pump-thaw cycles. The resulting mixturewas heated at 60° C. overnight and then allowed to cool to roomtemperature after which water was added (twice the volume of THF:H₂O 4:3used). The mixture was then extracted with dichloromethane (twice thevolume of THF:H₂O 4:3 used) and the organic extracts was dried withMgSO₄, filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel, eluting with EtOAc:hexanes (3:8 to 1:1(v/v)), to afford the pure cross-coupled product as a white solid (0.199g, 0.63 mmol, 57% yield). R_(f)=0.38 (EtOAc:hexanes 1:1 (v/v)). ¹H NMR(700 MHz, (CD₃)₂SO, 25° C., δ): 10.40 (s, 1H), 8.29 (d, J=2.58 Hz, 1H),8.03-7.99 (m, 2H), 7.89 (d, J=3.01 Hz, 1H), 7.73-7.70 (m, 2H), 7.68-7.63(m, 4H), 3.93 (s, 3H), 3.89 (s, 3H), 3.75 (s, 3H). ¹³C NMR (175 MHz,(CD₃)₂SO, ° C., δ): 165.6, 157.3, 155.2, 139.3, 136.4, 133.9, 132.5,131.7, 131.6, 129.5, 129.4, 127.0, 122.2, 121.1, 92.1, 89.2, 53.8, 53.1,52.4.

N-Hydroxy-N-(6-(((8R,9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl)oxy)pyridin-3-yl)acetamide(8x)

Under N₂ atmosphere, a solution of 2-fluoro-5-nitropyridine (0.320 g,2.22 mmol, 1.20 equiv) in DMF (8.50 mL, 0.261 M) was added to a mixtureof estrone (0.500 g, 1.85 mmol, 1.00 equiv) and Cs₂CO₃ (0.720 g, 2.22mmol, 1.20 equiv) in DMF (10.0 mL, 0.185 M) at 23° C. The resultingmixture was stirred at 23° C. for 12 h. The reaction mixture was pouredto LiCl solution (100 mL), extracted with EtOAc. The combined organiclayers was dried (MgSO₄), filtered and concentrated in vacuo. Theresidue was recrystalized from hexanes/EtOAc, to afford the titlecompound as a light yellow solid (0.650 g, 1.66 mmol, 89% yield).R_(f)=0.52 (hexanes:EtOAc 2:1 (v/v)). NMR Spectroscopy: 1H NMR (700 MHz,CDCl₃, 25° C., δ): 9.06 (d, J=2.58 Hz, 1H), 8.46 (dd, J=9.03, 2.58 Hz,1H), 7.36 (d, J=8.60 Hz, 1H), 7.03 (d, J=9.03 Hz, 1H), 6.93 (dd, J=8.60,2.58 Hz, 1H), 6.89 (d, J=2.58 Hz, 1H), 2.97-2.92 (m, 2H), 2.52 (dd,J=19.36, 8.60 Hz, 1H), 2.46-2.40 (m, 1H), 2.33 (td, J=11.19, 4.30 Hz,1H), 2.20-2.12 (m, 1H), 2.11-2.02 (m, 2H), 1.99 (dt, J=12.91, 3.01 Hz,1H), 1.68-1.45 (m, 6H), 0.93 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C.,δ): 220.9, 167.2, 150.7, 145.3, 140.3, 138.8, 137.7, 135.0, 127.0,121.5, 118.8, 111.5, 50.6, 48.1, 44.3, 38.1, 36.0, 31.7, 29.6, 26.5,25.9, 21.7, 14.0. Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd forC₂₃H₂₅N₂O₄ ([M+H]⁺), 393.1809, found, 393.1812.

Under N₂ atmosphere, a suspension of(8R,9S,13S,14S)-13-methyl-3-((5-nitropyridin-2-yl)oxy)-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one(300 mg, 0.760 mmol, 1.00 equiv) and 5% Rh/C (8.70 mg, 0.60 mol % Rh) inTHF (7.60 mL, 0.100 M) was stirred at 23° C. Hydrazine monohydrate (45.9mg, 0.910 mmol, 1.20 equiv) was added dropwise. The reaction mixture wasstirred at 23° C. for 20 min. NaHCO₃ (76.4 mg, 0.91 mmol, 1.20 equiv)was added, followed by dropwise addition of acetyl chloride (71.4 mg,0.91 mmol, 1.20 equiv) in THF (7.6 mL, 0.120 M). The reaction mixturewas stirred at 23° C. for 30 min and then filtered through a short padof celite. The celite was washed with EtOAc. The combined organicsolution was concentrated in vacuo. The residue was recrystalized fromhexanes/EtOAc, to afford the title compound as a yellow solid (310 mg,0.737 mmol, 97% yield). R_(f)=0.13 (hexanes:EtOAc 1:1 (v/v)). NMRSpectroscopy: ¹H NMR (700 MHz, (CD₃)₂SO, 25° C., δ): 10.76 (s, 1H), 8.34(d, J=1.83 Hz, 1H), 8.00 (dd, J=8.85, 2.44 Hz, 1H), 7.31 (d, J=8.54 Hz,1H), 7.01 (d, J=8.85 Hz, 1H), 6.86 (dd, J=8.24, 2.44 Hz, 1H), 6.81 (d,J=2.44 Hz, 1H), 2.87-2.80 (m, 2H), 2.50 (dt, J=3.66, 1.83 Hz, 3H),2.36-2.48 (m, 2H), 2.26 (br. s., 1H), 2.20 (br. s., 3H), 2.07 (dd,J=18.92, 8.85 Hz, 1H), 2.01-1.91 (m, 2H), 1.82-1.75 (m, 1H), 1.63-1.32(m, 6H), 0.85 (s, 3H). ¹³C NMR (175 MHz, (CD₃)₂SO, 25° C., δ): 219.7,170.5, 160.0, 151.9, 139.7, 138.0, 135.9, 134.2, 133.0, 126.6, 120.8,118.3, 110.9, 49.6, 47.3, 43.6, 37.6, 35.4, 31.4, 29.0, 25.9, 25.4,21.9, 21.2, 13.5. Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd forC₂₅H₂₉N₂O₄ ([M+H]⁺), 421.2122, found, 421.2125.

N-(6-((6R,12aR)-6-(Benzo[d][1,3]dioxol-5-yl)-2-methyl-1,4-dioxo-1,3,4,6,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indol-7 (2H)-yl)pyridin-3-yl)-N-hydroxyacetamide (8y)

Under N₂ atmosphere, to a mixture of (6R,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione(1.00 g, 2.60 mmol, 1.00 equiv) and K₂CO₃ (0.36 g, 2.60 mmol, 1.00equiv) in DMF (26.0 mL, 0.100 M) was added 2-fluoro-5-nitropyridine(0.550 g, 3.90 mmol, 1.50 equiv) and the reaction mixture was stirred at23° C. for 40 h. The reaction mixture was poured to water (100 mL),extracted with EtOAc, washed with brine. The combined organic layers wasdried (MgSO₄), filtered and concentrated in vacuo. The residue waspurified by chromatography on silica gel, eluting with hexanes:EtOAc(1:1 to 1:3 (v/v)), to afford the title compound as a yellow solid(0.810 g, 1.58 mmol, 61% yield) R_(f)=0.51 (EtOAc). NMR Spectroscopy: ¹HNMR (700 MHz, DMSO, 25° C., δ): 9.44 (d, J=2.58 Hz, 1H), 8.53 (dd,J=8.82, 2.80 Hz, 1H), 7.73-7.69 (m, 1H), 7.55-7.50 (m, 1H), 7.41 (d,J=9.03 Hz, 1H), 7.35-7.28 (m, 2H), 7.00 (s, 1H), 6.52-6.44 (m, 3H), 5.80(dd, J=6.45, 1.29 Hz, 2H), 4.38 (dd, J=11.62, 4.30 Hz, 1H), 4.16-4.10(m, 1H), 3.93 (d, J=17.21 Hz, 1H), 3.84 (dd, J=16.13, 4.52 Hz, 1H), 3.27(ddd, J=16.35, 11.62, 1.29 Hz, 1H), 3.06-3.01 (m, 3H). ¹³C NMR (175 MHz,CDCl₃, 25° C., δ): 166.5, 166.4, 154.6, 147.6, 147.0, 145.6, 141.6,136.6, 134.6, 134.0, 133.9, 127.6, 124.6, 122.8, 121.9, 119.6, 118.0,113.3, 110.9, 108.2, 107.8, 101.2, 55.6, 55.4, 52.4, 33.8, 23.9. MassSpectrometry: HRMS (ESI-TOF) (m/z): calcd for C₂₇H₂₂N₅O₆ ([M+H]⁺),512.1565, found, 512.1567. Under N₂ atmosphere, a suspension of(6R,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2-methyl-7-(5-nitropyridin-2-yl)-2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione(300 mg, 0.590 mmol, 1.00 equiv) and 5% Rh/C (6.80 mg, 0.60 mol % Rh) inTHF (5.90 mL, 0.100 M) was stirred at 23° C. Hydrazine monohydrate (35.4mg, 0.710 mmol, 1.20 equiv) was added dropwise. The reaction mixture wasstirred at 23° C. for 20 min. NaHCO₃ (59.6 mg, 0.710 mmol, 1.20 equiv)was added, followed by dropwise addition of a solution of acetylchloride (55.7 mg, 0.710 mmol, 1.20 equiv) in THF (5.90 mL, 0.120 M).The reaction mixture was stirred at 23° C. for 30 min and then filteredthrough a short pad of celite. The celite was washed with EtOAc. Thecombined organic solution was concentrated in vacuo. The residue wasrecrystalized from hexanes/EtOAc, to afford the title compound as awhite solid (320 mg, 0.59 mmol, quant yield). R_(f)=0.17 (EtOAc). NMRSpectroscopy: ¹H NMR (700 MHz, (CD₃)₂SO, 25° C., δ): 11.03 (br. s., 1H),8.96 (br. s., 1H), 8.22 (d, J=8.60 Hz, 1H), 7.78-7.70 (m, 1H), 7.43-7.34(m, 2H), 7.23-7.16 (m, 2H), 6.68 (br. s., 1H), 6.54-6.47 (m, 1H), 6.28(d, J=1.72 Hz, 1H), 6.19 (dd, J=8.17, 1.72 Hz, 1H), 5.84 (dd, J=12.91,2.58 Hz, 2H), 4.53 (d, J=11.62 Hz, 1H), 4.19 (d, J=16.78 Hz, 1H), 3.92(d, J=17.21 Hz, 1H), 3.66 (d, J=15.92 Hz, 1H), 2.97-2.87 (m, 3H),2.44-2.43 (m, 1H), 2.31 (br. s., 3H). ¹³C NMR (175 MHz, (CD₃)₂SO, 25°C., δ): 166.9, 166.4, 146.8, 146.0, 137.0, 136.4, 135.4, 134.6, 126.0,123.1, 120.9, 120.3, 119.5, 119.0, 110.3, 109.3, 107.5, 107.1, 100.9,54.9, 54.2, 51.5, 32.8, 23.3, 22.3. Mass Spectrometry: HRMS (ESI-TOF)(m/z): calcd for C₂₉H₂₆N₅O₆ ([M+H]⁺), 540.1878, found, 540.1881.

Methyl (5-bromo-6-methoxy-2-(trifluoromethoxy)pyridin-3-yl) carbamate(9a)

A solution of methyl (5-bromo-6-methoxypyridin-3-yl)(hydroxy)carbamate(8a) (50.0 mg, 0.180 mmol) and Togni reagent I (71.5 mg, 0.217 mmol,1.20 equiv) in CH₂Cl₂ (1.80 mL, 0.100 M) was stirred at 23° C. under N₂atmosphere for 16 h. The reaction mixture was purified by preparativeTLC (thickness: 1 mm) using hexanes:EtOAc (19:1 (v/v)) for development(prep TLC was developed three times).

The purification afforded the title compound as a white solid (47.3 mg,0.137 mmol, 76% yield). R_(f)=0.69 (EtOAc:hexanes 1:4 (v/v)). NMRSpectroscopy: ¹H NMR (500 MHz, CDCl₃, 25° C., δ): 8.65 (br. s, 1H), 6.62(br. s, 1H), 3.93 (s, 3H), 3.80 (s, 3H). ¹³C NMR (125 MHz, CDCl₃, ° C.,δ): 153.8, 153.6, 141.9, 135.6, 120.1 (q, J=261.6 Hz), 117.3, 102.6,55.1, 53.0. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −56.6 (s). MassSpectrometry: HRMS (ESI-TOF) (m/z): calcd for C₉H₉BrF₃N₂O₄ ([M+H]⁺),344.9692, found, 344.9705.

Methyl (5-iodo-6-methoxy-2-(trifluoromethoxy)pyridin-3-yl)carbamate (9b)

A solution of methyl hydroxy(5-iodo-6-methoxypyridin-3-yl)carbamate (9b)(50.0 mg, 0.154 mmol) and Togni reagent I (61.1 mg, 0.185 mmol, 1.20equiv) in CH₂Cl₂ (1.54 mL, 0.100 M) was stirred at 23° C. under N₂atmosphere for 18 h. The reaction mixture was purified by preparativeTLC (thickness: 1 mm) using hexanes:EtOAc (97:3 (v/v)) for development(prep TLC was developed six times). The purification afforded the titlecompound as a white solid (44.2 mg, 0.113 mmol, 73% yield). R_(f)=0.53(EtOAc:hexanes 1:9 (v/v)). NMR Spectroscopy: ¹H NMR (500 MHz, CDCl₃, 25°C., δ): 8.81 (br. s, 1H), 6.58 (br. s., 1H), 3.91 (s, 3H), 3.80 (s, 3H).¹³C NMR (125 MHz, CDCl₃, 25° C., δ): 155.8, 153.8, 143.4, 141.6, 120.1(q, J=261.8 Hz), 117.4, 73.9, 55.4, 52.9. ¹⁹F NMR (376 MHz, CDCl₃, 25°C., δ): −56.5 (s). Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd forC₉H₉F₃IN₂O₄ ([M+H]⁺), 392.9554, found, 392.9556.

Methyl (6-chloro-4-methyl-2-(trifluoromethoxy)pyridin-3-yl) carbamate(9c)

A solution of methyl (6-chloro-4-methylpyridin-3-yl)(hydroxy)carbamate(8c) (108 mg, 0.500 mmol) and Togni reagent I (198 mg, 0.600 mmol, 1.20equiv) in CH₂Cl₂ (5.00 mL, 0.100 M) was stirred at 23° C. under N₂atmosphere for 15 h. The reaction mixture was concentrated in vacuo. Theresidue was dissolved in MeNO₂ (5.00 mL, 0.100 M) and the reactionmixture was stirred at 120° C. for 15 h. The reaction mixture wasconcentrated in vacuo and purified by chromatography on silica gel,eluting with hexanes:EtOAc (8:1 to 4:1 (v/v)), to afford 2c (99.0 mg,0.348 mmol, 70% yield). Data for 9c: white solid; R_(f)=0.45(EtOAc:hexanes 1:4 (v/v)). NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃, 25°C., δ): 8.44 (d, J=8.53 Hz, 1H), 7.38 (d, J=8.53 Hz, 1H), 6.85 (br. s,1H), 3.83 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 154.4, 151.6,150.6, 145.5, 124.1, 120.0 (q, J=261.9 Hz), 119.9, 53.4 (d, J=7.51 Hz),18.4. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −57.0 (s). Mass Spectrometry:HRMS (ESI-TOF) (m/z): calcd for C₉H₉ClF₃N₂O₃ ([M+H]⁺), 285.0248, found,285.0249.

Methyl (6-bromo-2-(trifluoromethoxy)pyridin-3-yl) carbamate (9d) andmethyl (6-bromo-4-(trifluoromethoxy)pyridin-3-yl)carbamate (9d-II)

A solution of methyl (6-bromopyridin-3-yl)(hydroxy)carbamate (8d) (124mg, 0.226 mmol) and Togni reagent I (198 mg, 0.600 mmol, 1.20 equiv) inCH₂Cl₂ (5.00 mL, 0.100 M) was stirred at 23° C. under N₂ atmosphere for15 h. The reaction mixture was concentrated in vacuo. The residue wasdissolved in MeNO₂ (5.00 mL, 0.100 M) and the reaction mixture wasstirred at 120° C. for 15 h. The reaction mixture was concentrated invacuo and purified by chromatography on silica gel, eluting withhexanes:EtOAc (19:1 to 9:1 (v/v)), to afford 9d (91 mg, 0.289 mmol, 58%yield) and 9d-II (33 mg, 0.105 mmol, 21% yield). Data for 9d: whitesolid; R_(f)=0.57 (EtOAc:hexanes 1:4 (v/v)). NMR Spectroscopy: ¹H NMR(400 MHz, CDCl₃, 25° C., δ): 8.44 (d, J=8.53 Hz, 1H), 7.38 (d, J=8.53Hz, 1H), 6.85 (br. s, 1H), 3.83 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25°C., δ): 153.4, 143.8, 130.3, 129.6, 126.6, 123.5, 120.0 (q, J=265.2 Hz),53.2. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −56.7 (s). Mass Spectrometry:HRMS (ESI-TOF) (m/z): calcd for C₈H₇BrF₃N₂O₃ ([M+H]⁺), 314.9587, found,314.9585. Data for 9d-II: white solid; R_(f)=0.45 (EtOAc:hexanes 1:4(v/v)) NMR Spectroscopy: 1H NMR (400 MHz, CDCl₃, 25° C., δ): 9.23 (br.s, 1H), 7.35 (q, J=2.01 Hz, 1H), 6.77 (br. s, 1H), 3.84 (s, 3H). ¹³C NMR(175 MHz, CDCl₃, 25° C., δ): 153.1, 144.8, 142.7, 134.8, 126.5, 120.2(q, J=265.2 Hz), 116.9, 53.4. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −57.9(s). Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₈H₇BrF₃N₂O₃([M+H]⁺), 314.9587, found, 314.9586.

Methyl (6-fluoro-2-(trifluoromethoxy)pyridin-3-yl)carbamate (9e) andmethyl (6-fluoro-4-(trifluoromethoxy)pyridin-3-yl) carbamate (9e-II)

A solution of methyl (6-fluoropyridin-3-yl)(hydroxy)carbamate (8e) (93.1mg, 0.500 mmol) and Togni reagent I (198 mg, 0.600 mmol, 1.20 equiv) inCH₂Cl₂ (5.00 mL, 0.100 M) was stirred at 23° C. under N₂ atmosphere for20 h. The reaction mixture was concentrated in vacuo. The residue wasdissolved in MeNO₂ (5.00 mL, 0.100 M) and the reaction mixture wasstirred at 120° C. for 24 h. The crude residue was purified by flashchromatography eluting hexanes and then EtOAc:hexanes (1:4 (v/v)). Thepurification afforded a 1.6:1 mixture of 9e and 9e-II, which was furtherpurified by preparative TLC (thickness: 1 mm) using hexanes:EtOAc (19:1(v/v)) for development (prep TLC was developed five times). Thepurification afforded 9e (45.8 mg, 0.180 mmol, 36% yield) and 9e-II(28.7 mg, 0.113 mmol, 23% yield). Data for 9e: white solid; R_(f)=0.48(EtOAc:hexanes 1:4 (v/v)). NMR Spectroscopy: ¹H NMR (400 MHz, CDCl₃, 25°C., δ): 8.64 (br. s, 1H), 6.87 (dd, J=8.66, 3.14 Hz, 1H), 6.79 (br. s,1H), 3.83 (s, 3H). ¹³C NMR (124 MHz, CDCl₃, 25° C., δ): 155.6 (d,J=242.1 Hz), 153.7, 142.2, 133.5, 121.4, 120.0 (q, J=262.7 Hz), 107.1(d, J=35.6 Hz), 53.1. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −56.8 (s),−75.7 (s). Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₈H₇F₄N₂O₃([M+H]⁺), 255.0387, found, 255.0387. Data for 9e-II: off-white solid;R_(f)=0.44 (EtOAc:hexanes 1:4 (v/v)). NMR Spectroscopy: ¹H NMR (400 MHz,CDCl₃, ° C., δ): 8.98 (br. s, 1H), 6.83 (quin, J=2.13 Hz, 1H), 6.69 (br.s, 1H), 3.83 (s, 3H). ¹³C NMR (125 MHz, CDCl₃, 25° C., δ): 159.2 (d,J=234.5 Hz), 153.5, 147.5, 140.3, 124.6, 120.2 (q, J=262.2 Hz), 99.2 (d,J=45.2 Hz), 53.3. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −58.2 (s), −69.6(s). Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₈H₇F₄N₂O₃([M+H]⁺), 255.0387, found, 255.0390.

Methyl (5-bromo-6-chloro-2-(trifluoromethoxy)pyridin-3-yl)carbamate (9f)and methyl (5-Bromo-6-chloro-4-(trifluoromethoxy)pyridin-3-yl)carbamate(9f-II)

A solution of methyl (5-bromo-6-chloropyridin-3-yl)(hydroxy)carbamate(8f) (141 mg, 0.500 mmol) and Togni reagent I (198 mg, 0.600 mmol, 1.20equiv) in CH₂Cl₂ (5.00 mL, 0.100 M) was stirred at 23° C. under N₂atmosphere for 18 h. The reaction mixture was concentrated in vacuo. Theresidue was dissolved in MeNO₂ (5.00 mL, 0.100 M) and the reactionmixture was stirred at 120° C. for 24 h. The crude residue was purifiedby flash chromatography eluting with EtOAc:hexanes (1:19 to 1:4 (v/v)),to afford 9f (75.6 mg, 0.216 mmol, 43% yield) and 9f-II (34.6 mg, 0.0990mmol, 20% yield). Data for 9f: white solid; R_(f)=0.52 (EtOAc:hexanes1:4 (v/v)). NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃, 25° C., δ): 8.86(s, 1H), 6.85 (br. s, 1H), 3.84 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25°C., δ): 153.2, 142.3, 139.7, 133.3, 123.7, 119.9 (q, J=263.4 Hz), 117.6,53.4. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −56.8 (s). Mass Spectrometry:HRMS (ESI-TOF) (m/z): calcd for C₈H₆BrClF₃N₂O₃ ([M+H]⁺), 348.9197,found, 348.9196. Data for 9f-II: slightly yellow solid; R_(f)=0.43(EtOAc:hexanes 1:4 (v/v)). NMR Spectroscopy: ¹H NMR (500 MHz, CDCl₃, 25°C., δ): 9.19 (br. s, 1H), 6.78 (br. s, 1H), 3.84 (s, 3H). ¹³C NMR (125MHz, CDCl₃, 25° C., δ): 153.1, 146.4, 143.8, 140.9, 129.5, 120.5 (q,J=263.7 Hz), 116.4, 53.6. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −55.5(s). Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₈H₆BrClF₃N₂O₃([M+H]⁺), 348.9197, found, 348.9198.

Methyl (2-chloro-4-(trifluoromethoxy)pyridin-3-yl) carbamate (9g)

A solution of methyl (2-chloropyridin-3-yl)(hydroxy)carbamate (8g) (101mg, 0.500 mmol) and Togni reagent I (198 mg, 0.600 mmol, 1.20 equiv) inCH₂Cl₂ (5.00 mL, 0.100 M) was stirred at 23° C. under N₂ atmosphere for15 h. The reaction mixture was concentrated in vacuo. The residue wasdissolved in MeNO₂ (5.00 mL, 0.100 M) and the reaction mixture wasstirred at 120° C. for 15 h. The reaction mixture was concentrated invacuo and purified by chromatography on silica gel, eluting withhexanes:EtOAc (10:1 to 5:1 (v/v)), to afford 9g (73.0 mg, 0.270 mmol,53% yield) and 9g′ (45.0 mg, 0.166 mmol, 33% yield). Data for 9g: whitesolid; R_(f)=0.72 (EtOAc:hexanes 1:4 (v/v)). NMR Spectroscopy: ¹H NMR(700 MHz, CDCl₃, 25° C., δ): 8.10 (d, J=5.59 Hz, 1H) 7.31 (d, J=5.16 Hz,1H) 6.25 (br. s, 1H) 3.80 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ):153.9, 153.1, 145.0, 143.8, 123.3, 120.8, 120.1 (q, J=261.6 Hz), 53.4.¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −57.3 (s). Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₈HClF₃N₂O₃ ([M+H]⁺), 271.0092, found,271.0093. Data for 9g′: white solid; R_(f)=0.48 (EtOAc:hexanes 1:4(v/v)) NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃, 25° C., δ): 8.32 (d,J=5.59 Hz, 1H) 7.23-7.20 (m, 1H) 6.28 (br. s, 1H) 3.80 (s, 3H). ¹³C NMR(175 MHz, CDCl₃, 25° C., δ): 153.9, 152.8, 150.6, 148.2, 123.3, 120.2(q, J=261.5 Hz), 113.3, 53.5. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −58.4(s). Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₈H₇ClF₃N₂O₃([M+H]⁺), 271.0092, found, 271.0095.

N-(2,6-Dichloro-4-(trifluoromethoxy)pyridin-3-yl)acetamide (9h)

A solution of N-(2,6-dichloropyridin-3-yl)-N-hydroxyacetamide (8h) (50.0mg, 0.226 mmol) and Togni reagent I (89.5 mg, 0.271 mmol, 1.20 equiv) inCH₂Cl₂ (2.26 mL, 0.100 M) was stirred at 23° C. under N₂ atmosphere for16 h. The reaction mixture was concentrated in vacuo. The residue wasdissolved in MeNO₂ (2.26 mL, 0.100 M) and the reaction mixture wasstirred at 120° C. for 22 h. The reaction mixture was purified bypreparative TLC (thickness: 1 mm) using hexanes:EtOAc (17:3 (v/v)) fordevelopment (prep TLC was developed five times) followed byrecrystallization from Et₂O:hexanes. The purification afforded the titlecompound as a 1.4:1 mixture of atropisomers (45.8 mg, 0.158 mmol, 70%yield). The products could not readily be separated by silica gelchromatography or preparative TLC, so they were characterized as amixture. Data for the mixture of 9h: white solid; R_(f)=0.48 and 0.59(EtOAc:hexanes 2:3 (v/v)). ¹H NMR (500 MHz, CDCl₃, 25° C., δ): 7.36 (s,1H), 7.24 (q, J=1.8 Hz, 1H), 6.91 (br. s, 1H), 6.89 (br. s, 1H), 2.23(s, 3H), 2.22 (s, 3H). ¹³C NMR (125 MHz, CDCl₃, 25° C., δ): 168.3,153.9, 151.8, 149.4, 149.1, 146.8, 145.9, 123.1, 122.4, 120.0 (q,J=262.1 Hz), 119.9 (q, J=263.1 Hz), 119.5, 113.7, 23.1. ¹⁹F NMR (376MHz, CDCl₃, 25° C., δ): −56.8 (s), −57.9 (s). Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₈H₆Cl₂F₃N₂O₂ ([M+H]⁺), 288.9753, found,288.9756.

N-(6-Methoxy-4-methyl-2-(trifluoromethoxy)pyridin-3-yl)acetamide (9i)

A solution of N-hydroxy-N-(6-methoxy-4-methylpyridin-3-yl)acetamide (8i)(50.0 mg, 0.255 mmol) and Togni reagent I (101 mg, 0.306 mmol, 1.20equiv) in CH₂Cl₂ (2.55 mL, 0.100 M) was stirred at 23° C. under N₂atmosphere for 18 h. The reaction mixture was purified by preparativeTLC (thickness: 1 mm) using hexanes:EtOAc (3:2 (v/v)) for development(prep TLC was developed five times). The purification afforded the titlecompound as a white solid (54.5 mg, 0.206 mmol, 81% yield). R_(f)=0.63(EtOAc:hexanes 3:2 (v/v)). NMR Spectroscopy (at rt, a mixture ofrotamers was observed: ¹H NMR (400 MHz, CDCl₃, 60° C., δ): 6.89 (br. s,1H), 6.49 (br. s, 1H), 3.86 (s, 3H), 2.20 (br. s, 3H), 2.14 (br. s, 3H).¹³C NMR (100 MHz, CDCl₃, 60° C., δ): 169.3, 161.0, 152.1, 150.1, 120.4(q, J=260.2 Hz), 113.9, 109.2, 54.0, 23.0, 18.3. ¹⁹F NMR (376 MHz,CDCl₃, 60° C., δ): −56.4 (s). Mass Spectrometry: HRMS (ESI-TOF) (m/z):calcd for C₁₀H₁₂F₃N₂O₃ ([M+H]⁺), 265.0795, found, 265.0801.

N-(6-Methyl-2-(trifluoromethoxy)pyridin-3-yl)acetamide (9j)

A solution of N-hydroxy-N-(6-methylpyridin-3-yl)acetamide (8j) (50.0 mg,0.301 mmol) and Togni reagent I (119.2 mg, 0.361 mmol, 1.20 equiv) inCH₂Cl₂ (3.01 mL, 0.100 M) was stirred at 23° C. under N₂ atmosphere for21 h. The reaction mixture was concentrated in vacuo. The residue wasdissolved in MeNO₂ (3.01 mL, 0.100 M) and the reaction mixture wasstirred at 120° C. for 15 h. The reaction mixture was purified bypreparative TLC (thickness: 1 mm) using hexanes:EtOAc (4:1 (v/v)) fordevelopment (prep TLC was developed four times). The purificationafforded the title compound as a white solid (35.8 mg, 0.153 mmol, 51%yield). R_(f)=0.24 (EtOAc:hexanes 4:1 (v/v)). ¹H NMR (400 MHz, CDCl₃,25° C., δ): 8.57 (d, J=8.28 Hz, 1H), 7.39 (br. s, 1H), 7.02 (d, J=8.28Hz, 1H), 2.44 (s, 3H), 2.22 (s, 3H). ¹³C NMR (125 MHz, CDCl₃, 60° C.,δ): 168.8, 151.1, 144.7, 130.5, 121.6, 121.1, 120.2 (q, J=261.0 Hz),24.8, 23.4. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −56.1 (s). MassSpectrometry: HRMS (ESI-TOF) (m/z): calcd for C₉H₁₀F₃N₂O₂ ([M+H]⁺),235.0689, found, 235.0690.

Methyl (5-(2,4-difluorophenyl)-6-methoxy-2-(trifluoromethoxy)pyridin-3-yl)carbamate (9k)

A solution of methyl(5-(2,4-difluorophenyl)-6-methoxypyridin-3-yl)(hydroxy)carbamate (8k)(50.0 mg, 0.161 mmol) and Togni reagent I (63.8 mg, 0.193 mmol, 1.20equiv) in CH₂Cl₂ (1.58 mL, 0.100 M) was stirred at 23° C. under N₂atmosphere for 15 h. The reaction mixture was purified by preparativeTLC (thickness: 1 mm) using hexanes:EtOAc (19:1 (v/v)) for development(prep TLC was developed 3x). The purification afforded the titlecompound as a white solid (46.6 mg, 0.123 mmol, 77% yield). R_(f)=0.60(EtOAc:hexanes 1:4 (v/v)). ¹H NMR (700 MHz, CDCl₃, 25° C., δ): 8.38 (br.s., 1H), 7.35 (td, J=8.41, 6.53 Hz, 1H), 6.97-6.85 (m, 2H), 6.65 (br. s,1H), 3.88 (s, 3H), 3.79 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ):163.0 (dd, J=248.1 Hz, J=11.6 Hz), 160.2 (dd, J=249.4 Hz, J=11.5 Hz),154.7, 154.0, 142.8, 134.3, 132.6 (m), 120.3 (q, J=261.0 Hz), 119.4 (dd,J=15.3 Hz, J=3.8 Hz), 116.2, 115.6, 111.4 (dd, J=21.2 Hz, J=3.1 Hz),104.3 (t, J=25.5 Hz), 54.5, 52.9. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ):−56.4 (s), −110.3 (s), −110.5 (s). Mass Spectrometry: HRMS (ESI-TOF)(m/z): calcd for C₁₅H₁₂F₅N₂O₄ ([M+H]⁺), 379.0712, found, 379.0719.

Methyl(6-(4-(tert-butyl)phenoxy)-2-(trifluoromethoxy)pyridin-3-yl)carbamate(91)

A solution of methyl(6-(4-(tert-butyl)phenoxy)pyridin-3-yl)(hydroxy)carbamate (81) (50.0 mg,0.158 mmol) and Togni reagent I (62.9 mg, 0.190 mmol, 1.20 equiv) inCH₂Cl₂ (1.58 mL, 0.100 M) was stirred at 23° C. under N₂ atmosphere for16 h. The reaction mixture was purified by preparative TLC (thickness: 1mm) using hexanes:EtOAc (19:1 (v/v)) for development (prep TLC wasdeveloped four times). The purification afforded the title compound as acolorless oil (38.1 mg, 0.0991 mmol, 63% yield). R_(f)=0.57(EtOAc:hexanes 1:4 (v/v)). ¹H NMR (400 MHz, CDCl₃, 25° C., δ): 8.43 (br.s, 1H), 7.45-7.33 (m, 2H), 7.12-7.00 (m, 2H), 6.71 (app. d, J=8.8 Hz,2H), 3.80 (s, 3H), 1.33 (s, 9H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ):156.7, 153.9, 151.6, 147.9, 143.1, 132.9, 126.6, 120.2, 120.1 (q,J=261.6 Hz), 118.4, 108.3, 52.9, 34.6, 31.6. ¹⁹F NMR (376 MHz, CDCl₃,25° C., δ): −56.6 (s). Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcdfor C₁₈H₂₀F₃N₂O₄ ([M+H]⁺), 385.1370, found, 385.1375.

Methyl (5-(5-formylfuran-2-yl)-6-methoxy-2-(trifluoromethoxy)pyridin-3-yl)carbamate (9m)

A solution of methyl(5-(5-formylfuran-2-yl)-6-methoxypyridin-3-yl)(hydroxy)carbamate (8m)(31.6 mg, 0.108 mmol) and Togni reagent I (42.9 mg, 0.130 mmol, 1.20equiv) in CH₂Cl₂ (1.08 mL, 0.100 M) was stirred at 23° C. under N₂atmosphere for 16 h. The reaction mixture was purified by preparativeTLC (thickness: 1 mm) using hexanes:EtOAc (3:2 (v/v)) for development(prep TLC was developed twice). The purification afforded the titlecompound as an off-white solid (24.8 mg, 0.0688 mmol, 64% yield).R_(f)=0.50 (EtOAc:hexanes 3:7 (v/v)). NMR Spectroscopy: ¹H NMR (700 MHz,CDCl₃, 25° C., δ): 9.70 (s, 1H), 8.94 (br. s, 1H), 7.32 (d, J=3.44 Hz,1H), 7.13 (d, J=3.44 Hz, 1H), 6.68 (br. s, 1H), 4.03 (s, 3H), 3.83 (s,3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 177.9, 154.0, 153.9, 153.2,152.0, 143.2, 130.2, 122.4, 120.1 (q, J=261.8 Hz), 116.7, 113.1, 110.6,54.7, 53.0. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −56.4 (s). MassSpectrometry: HRMS (ESI-TOF) (m/z): calcd for C₁₄H₁₂F₃N₂O₆ ([M+H]⁺),361.0642, found, 361.0643.

N-(6-(1H-Pyrazol-1-yl)-2-(trifluoromethoxy)pyridin-3-yl)acetamide (9n)

A solution of N-(6-(1H-pyrazol-1-yl)pyridin-3-yl)-N-hydroxyacetamide(8n) (50.0 mg, 0.229 mmol) and Togni reagent I (90.8 mg, 0.275 mmol,1.20 equiv) in CH₂Cl₂ (2.29 mL, 0.100 M) was stirred at 23° C. under N₂atmosphere for 18 h. The reaction mixture was purified by preparativeTLC (thickness: 1 mm) using hexanes:EtOAc (9:1 (v/v)) for development(prep TLC was developed three times). The purification afforded thetitle compound as a white solid (58.0 mg, 0.203 mmol, 89% yield).R_(f)=0.30 (EtOAc:hexanes 3:7 (v/v)). NMR Spectroscopy: ¹H NMR (400 MHz,CDCl₃, 25° C., δ): 8.85 (d, J=8.60 Hz, 1H), 8.34 (d, J=2.58 Hz, 1H),7.83 (d, J=9.03 Hz, 1H), 7.70 (s, 1H), 7.43 (br. s, 1H), 6.43 (m, 1H),2.25 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 168.6, 143.9, 143.5,142.5, 133.2, 127.2, 120.9, 120.2 (q, J=262.1 Hz), 109.8, 108.2, 24.8.¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −56.5 (s). Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₁₁H₁₀F₃N₄O₂ ([M+H]⁺), 287.0750, found,275.0754.

Methyl(6-(1H-1,2,4-triazol-1-yl)-2-(trifluoromethoxy)pyridin-3-yl)carbamate(9o) and methyl(6-(1H-1,2,4-triazol-1-yl)-4-(trifluoromethoxy)pyridin-3-yl)carbamate(9o-II)

A solution of methyl(6-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)(hydroxy)carbamate (8o) (100 mg,0.425 mmol) and Togni reagent I (168 mg, 0.510 mmol, 1.20 equiv) inCH₂Cl₂ (4.25 mL, 0.100 M) was stirred at 23° C. under N₂ atmosphere for18 h. The reaction mixture was concentrated in vacuo. The residue wasdissolved in MeNO₂ (4.25 mL, 0.100 M) and the reaction mixture wasstirred at 80° C. for 4 h. The reaction mixture was placed in thefreezer. The solid was filtered and washed with hexanes. Filtrationafforded 2o (61.7 mg, 0.203 mmol, 48% yield) as a slightly brown solid.The filtrate was concentrated in vacuo and purified by preparative TLC(thickness: 1 mm) using hexanes:Et₂O (7:3 (v/v)) for development (prepTLC was developed six times). The purification afforded 9o (3.7 mg,0.0122 mmol, 3%) and 9.3 mg (0.0307 mmol, 7% yield) of a 1:4.6 mixtureof 9o and 9o-II. The combined reaction yield was 58%. Thecharacterization data for 9o-II was obtained by further purification ofthe mixture by preparative TLC using hexanes:EtOAc (7:3 (v/v)) fordevelopment (prep TLC was developed six times). Data for 9o: whitesolid; R_(f)=0.41 (EtOAc:hexanes 1:1 (v/v)). NMR Spectroscopy: ¹H NMR(500 MHz, CDCl₃, ° C., δ): 8.95 (s, 1H), 8.75 (d, J=7.93 Hz, 1H), 8.08(s, 1H), 7.80 (d, J=8.54 Hz, 1H), 7.00 (br. s, 1H), 3.85 (s, 3H). ¹³CNMR (125 MHz, CDCl₃, 25° C., δ): 153.5, 153.2, 143.2, 141.4, 140.6,131.4, 123.0, 120.1 (q, J=262.8 Hz), 110.9, 53.2. ¹⁹F NMR (376 MHz,CDCl₃, 25° C., δ): −56.7 (s). Mass Spectrometry: HRMS (ESI-TOF) (m/z):calcd for C₁₀H₉F₃N₅O₃ ([M+H]⁺), 304.0652, found, 304.0658. Data for9o-II: white solid; R_(f)=0.27 (EtOAc:hexanes 1:1 (v/v)). NMRSpectroscopy: ¹H NMR (700 MHz, CDCl₃, 25° C., δ): 9.30 (br. s, 1H), 9.14(s, 1H), 8.08 (s, 1H), 7.81 (s, 1H), 6.88 (br. s, 1H), 3.83 (s, 3H). ¹³CNMR (175 MHz, CDCl₃, 25° C., δ): 153.3, 153.0, 145.9, 145.3, 141.8,141.2, 126.1, 120.3 (q, J=262.0 Hz), 102.7, 53.4. ¹⁹F NMR (376 MHz,CDCl₃, 25° C., δ): −57.3 (d). Mass Spectrometry: HRMS (ESI-TOF) (m/z):calcd for C₁₀H₉F₃N₅O₃ ([M+H]⁺), 304.0652, found, 304.0657.

N-(6-(1H-Benzo[d]imidazol-1-yl)-2-(trifluoromethoxy)pyridin-3-yl)acetamide (9p)

A solution ofN-(6-(1H-benzo[d]imidazol-1-yl)pyridin-3-yl)-N-hydroxyacetamide (8p)(100 mg, 0.373 mmol) and Togni reagent I (148 mg, 0.448 mmol, 1.20equiv) in CH₂Cl₂ (3.73 mL, 0.100 M) was stirred at 23° C. under N₂atmosphere for 19 h. The reaction mixture was concentrated in vacuo (toabout 10% initial volume) and the residue was triturated with hexanes.The purification afforded the title compound as a beige solid (117 mg,0.348 mmol, 93% yield). R_(f)=0.21 (EtOAc:hexanes 4:1 (v/v)). NMRSpectroscopy: ¹H NMR (700 MHz, CDCl₃, 25° C., δ): 9.00 (d, J=8.60 Hz,1H), 8.52 (s, 1H), 8.04 (d, J=8.17 Hz, 1H), 7.86 (d, J=7.74 Hz, 1H),7.60 (br. s, 1H), 7.49 (d, J=8.60 Hz, 1H), 7.43-7.35 (m, 2H), 2.31 (s,3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 168.9, 144.3, 144.2, 141.8,140.9, 133.1, 131.9, 124.8, 123.9, 121.5, 120.7, 120.2 (q, J=262.4 Hz),112.8, 111.6, 24.9. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −56.5 (s). MassSpectrometry: HRMS (ESI-TOF) (m/z): calcd for C₁₅H₁₂F₃N₄O₂ ([M+H]⁺),337.0907, found, 337.0910.

N-(6-(1H-Benzo[d] [1,2,3]triazol-1-yl)-2-(trifluoromethoxy)pyridin-3-yl)acetamide (9q)

A solution of N-(6-(1H-benzo[d][1,2,3]triazol-1-yl)pyridin-3-yl)-N-hydroxyacetamide (8q) (100 mg, 0.371mmol) and Togni reagent I (147 mg, 0.445 mmol, 1.20 equiv) in CH₂Cl₂(3.71 mL, 0.100 M) was stirred at 23° C. under N₂ atmosphere for 18 h.The reaction mixture was then stirred at 50° C. for 4 h. The reactionmixture was concentrated in vacuo and the residue was triturated withhexanes. The purification afforded the title compound as a slightlyyellow solid (108 mg, 0.319 mmol, 86% yield). R_(f)=0.37 (EtOAc:hexanes2:3 (v/v)). NMR Spectroscopy: ¹H NMR (400 MHz, (CD₃)₂SO, 25° C., δ):10.04 (s, 1H), 8.73 (d, J=8.53 Hz, 1H), 8.42-8.32 (m, 1H), 8.30-8.18 (m,2H), 7.77 (t, J=7.65 Hz, 1H), 7.63-7.51 (m, 1H), 2.18 (s, 3H). ¹³C NMR(175 MHz, (CD₃)₂SO, 25° C., δ): 169.4, 146.0, 144.9, 142.7, 136.8,130.5, 129.6, 125.5, 122.5, 119.9, 119.8 (q, J=260.0 Hz), 113.0, 112.6,23.6. ¹⁹F NMR (376 MHz, (CD₃)₂SO, 25° C., δ): −57.0 (s). MassSpectrometry: HRMS (ESI-TOF) (m/z): calcd for C₁₄H₁₁F₃N₅O₂ ([M+H]⁺),338.0859, found, 338.0860.

N-(6-(5-Fluoro-1H-indol-1-yl)-2-(trifluoromethoxy)pyridin-3-yl)acetamide(9r)

A solution ofN-(6-(5-fluoro-1H-indol-1-yl)pyridin-3-yl)-N-hydroxyacetamide (8r) (50.0mg, 0.175 mmol) and Togni reagent I (69.3 mg, 0.210 mmol, 1.20 equiv) inCH₂Cl₂ (1.75 mL, 0.100 M) was stirred at 23° C. under N₂ atmosphere for15 h. The reaction mixture was concentrated in vacuo. The crude residuewas triturated with hexanes. The crude residue was purified by flashchromatography eluting with EtOAc:hexanes (3:17 to 1:1 (v/v). Thepurification afforded the title compound as a yellow solid (45.0 mg,0.127 mmol, 73% yield). R_(f)=0.36 (EtOAc:hexanes 2:3 (v/v)). NMRSpectroscopy: ¹H NMR (400 MHz, CDCl₃, 25° C., δ): 8.89 (d, J=8.78 Hz,1H), 8.20 (dd, J=9.03, 4.52 Hz, 1H), 7.64 (d, J=3.51 Hz, 1H), 7.35 (br.s, 1H), 7.32 (d, J=8.78 Hz, 2H), 7.28 (dd, J=9.29, 2.51 Hz, 1H), 7.04(td, J=9.10, 2.64 Hz, 1H), 6.67 (d, J=3.51 Hz, 1H), 2.29 (s, 3H). ¹³CNMR (175 MHz, CDCl₃, 25° C., δ): 168.7, 158.8 (d, J=236.1 Hz), 144.8,143.9, 133.0, 131.6, 131.1 (d, J=10.0 Hz), 126.9, 120.2 (q, J=262.1 Hz),119.6, 114.4 (d, J=9.1 Hz), 111.7 (d, J=25.2 Hz), 111.0, 106.3 (m),106.2, 24.9. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −56.4 (s), −122.9 (m).Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₁₆H₁₂F₄N₃O₂([M+H]⁺), 354.0860, found, 354.0865.

N-(6-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-(trifluoromethoxy)pyridin-3-yl)acetamide (9s)

A solution ofN-(6-(5-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-3-yl)-N-hydroxyacetamide(8s) (50.0 mg, 0.144 mmol) and Togni reagent I (57.1 mg, 0.172 mmol,1.20 equiv) in CH₂Cl₂ (1.44 mL, 0.100 M) was stirred at 23° C. under N₂atmosphere for 20 h. The reaction mixture was concentrated in vacuo. Thecrude residue was purified by flash chromatography eluting withEtOAc:hexanes (1:19 to 2:3 (v/v)). The crude product was triturated withhaxanes. The purification afforded the title compound as a white solid(38.2 mg, 0.0920 mmol, 64% yield). R_(f)=0.39 (EtOAc:hexanes 3:7 (v/v)).NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃, ° C., δ): 8.89 (d, J=9.03 Hz,1H), 8.81 (d, J=8.60 Hz, 1H), 8.41 (d, J=2.15 Hz, 1H), 8.19 (d, J=3.87Hz, 1H), 8.05 (d, J=2.15 Hz, 1H), 7.34 (br. s, 1H), 6.57 (d, J=3.87 Hz,1H), 2.28 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 168.5, 145.8,144.0, 143.5, 142.6, 133.0, 131.4, 127.5, 125.0, 120.2 (q, J=261.8 Hz),120.0, 113.6, 112.7, 102.6, 24.9. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ):−56.4 (s). Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd forC₁₅H₁₁BrF₃N₄O₂ ([M+H]⁺), 415.0012, found, 415.0018.

N-(6-(2-(Thiazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2-(trifluoromethoxy)pyridin-3-yl)acetamide (9t)

A solution ofN-hydroxy-N-(6-(2-(thiazol-4-yl)-1H-benzo[d]imidazol-1-yl)pyridin-3-yl)acetamide(8t) (100 mg, 0.285 mmol) and Togni reagent I (113 mg, 0.188 mmol, 1.20equiv) in CH₂Cl₂ (2.85 mL, 0.100 M) was stirred at 23° C. under N₂atmosphere for 20 h. The reaction mixture was then stirred at 50° C. for4 h. The reaction mixture was concentrated in vacuo and the residue wastriturated with hexanes. The purification afforded the title compound asa beige solid (113 mg, 0.270 mmol, 95% yield). R_(f)=0.42 (EtOAc). ¹HNMR (700 MHz, (CD₃)₂SO, 25° C., δ): 10.00 (s, 1H), 9.05 (s, 1H), 8.64(d, J=8.60 Hz, 1H), 8.48 (s, 1H), 7.82 (d, J=7.31 Hz, 1H), 7.55 (d,J=8.17 Hz, 1H), 7.47 (d, J=7.31 Hz, 1H), 7.40-7.30 (m, 2H), 2.18 (s,3H). ¹³C NMR (175 MHz, (CD₃)₂SO, 25° C., δ): 169.5, 154.8, 146.6, 145.8,145.0, 142.3, 141.2, 135.2, 135.1, 124.1, 123.5, 123.4, 122.7, 119.8,119.6, 119.5 (q, J=260.0 Hz), 110.8, 23.6. ¹⁹F NMR (376 MHz, (CD₃)₂SO,25° C., δ): −57.2 (s). Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcdfor C₁₈H₁₃F₃N₅O₂S ([M+H]⁺), 420.0737, found, 420.0738.

N-(6-(2,6-Dichloro-9H-purin-9-yl)-2-(trifluoromethoxy)pyridin-3-yl)acetamide(9u) andN-(6-(2,6-dichloro-9H-purin-9-yl)-4-(trifluoromethoxy)pyridin-3-yl)acetamide(9u-II)

A solution ofN-(6-(2,6-dichloro-9H-purin-9-yl)pyridin-3-yl)-N-hydroxyacetamide (8u)(38.4 mg, 0.113 mmol) and Togni reagent I (44.9 mg, 0.136 mmol, 1.20equiv) in CH₂Cl₂ (1.13 mL, 0.100 M) was stirred at 23° C. under N₂atmosphere for 20 h. The reaction mixture was concentrated in vacuo. Theresidue was dissolved in MeNO₂ (1.13 mL, 0.100 M) and the reactionmixture was stirred at 60° C. for 18 h. The reaction mixture wasconcentrated in vacuo. The residue was purified by preparative TLC(thickness: 1 mm) using hexanes:EtOAc (1:1 (v/v)) for development (prepTLC was developed three times). The purification afforded 9u (39.0 mg,0.0968 mmol, 85% yield) and 9u-II (3.3 mg, 0.0081 mmol, 7% yield). Datafor 9u: white solid; R_(f)=0.44 (EtOAc:hexanes 1:1 (v/v)). NMRSpectroscopy: ¹H NMR (700 MHz, CDCl₃, ° C., δ): 9.11 (d, J=8.60 Hz, 1H),8.94 (s, 1H), 8.47 (d, J=8.60 Hz, 1H), 7.53 (s, 1H), 2.31 (s, 3H). ¹³CNMR (175 MHz, CDCl₃, 25° C., δ): 168.8, 153.9, 152.6, 151.7, 143.6,143.5, 138.4, 133.1, 132.3, 123.2, 120.1 (q, J=263.4 Hz), 113.1, 24.9.¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −56.7 (s). Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₁₃H₈Cl₂F₃N₆O₂ ([M+H]⁺), 407.0032, found,407.0037. Data for 9u-II: white solid; R_(f)=0.22 (EtOAc:hexanes 1:1(v/v)). NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃, 25° C., δ): 9.60 (s,1H), 9.20 (s, 1H), 8.67 (d, J=1.72 Hz, 1H), 7.39 (br. s, 1H), 2.33 (s,3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 168.4, 153.9, 152.7, 151.6,145.8, 143.9, 143.3, 142.9, 132.4, 126.2, 120.4 (q, J=262.3 Hz), 104.6,24.7. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −57.9 (s). Mass Spectrometry:HRMS (ESI-TOF) (m/z): calcd for C₁3H₈Cl₂F₃N₆O₂ ([M+H]⁺), 407.0032,found, 407.0035.

Ethyl(E)-3-(4-fluoro-3-(2-methoxy-5-((methoxycarbonyl)amino)-6-(trifluoromethoxy)pyridin-3-yl) phenyl)acrylate (9v)

A solution of ethyl (E)-3-(4-fluoro-3-(5-(hydroxy(methoxycarbonyl)amino)-2-methoxypyridin-3-yl)phenyl) acrylate (8v) (46.1 mg, 0.118 mmol)in CH₂Cl₂ (11.3 mL) was cooled to 4° C. A solution of Togni reagent I(46.9 mg, 0.142 mmol, 1.20 equiv) in CH₂Cl₂ (0.500 mL) was then addeddropwise and the reaction mixture was stirred at 4° C. for 29 h. Thereaction mixture was concentrated in vacuo. The residue was purified bypreparative TLC (thickness: 1 mm) using hexanes:EtOAc (9:1 (v/v)) fordevelopment (prep TLC was developed four times). The purificationafforded the title compound as a white solid (28.5 mg, 0.0622 mmol, 53%yield). R_(f)=0.62 (EtOAc:hexanes 3:7 (v/v)). NMR Spectroscopy: ¹H NMR(700 MHz, CDCl₃, 25° C., δ): 8.44 (br. s, 1H), 7.66 (d, J=15.92 Hz, 1H),7.57-7.50 (m, 2H), 7.15 (t, J=9.03 Hz, 1H), 6.68 (br. s, 1H), 6.38 (d,J=15.92 Hz, 1H), 4.26 (q, J=6.88 Hz, 2H), 3.89 (s, 3H), 3.80 (s, 3H),1.33 (t, J=7.10 Hz, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 166.9,161.1 (d, J=252.7 Hz), 154.6, 154.0, 143.2, 134.2, 131.7 (d, J=2.6 Hz),130.9 (d, J=3.3 Hz), 129.6 (d, J=8.7 Hz), 124.0 (J=15.6 Hz), 120.3 (q,J=261.5 Hz), 118.6 (d, J=1.8 Hz), 116.7, 116.6, 116.3, 115.7, 60.7,54.5, 52.9, 14.4. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −56.4 (s), −111.4(s). Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₂₀H₁₉F₄N₂O₆([M+H]⁺), 459.1174, found, 459.1184.

Methyl4-((4-(2-methoxy-5-((methoxycarbonyl)amino)-6-(trifluoro-methoxy)pyridin-3-yl)phenyl)ethynyl)benzoate(9w)

A solution of methyl4-((4-(5-(hydroxy(methoxycarbonyl)amino)-2-methoxypyridin-3-yl)phenyl)ethynyl)benzoate(8w) (50.0 mg, 0.116 mmol) and Togni reagent I (45.9 mg, 0.139 mmol,1.20 equiv) in CH₂Cl₂ (1.16 mL, 0.100 M) was stirred at 23° C. under N₂atmosphere for 18 h. The reaction mixture was purified by preparativeTLC (thickness: 1 mm) using CH₂Cl₂ for development (prep TLC wasdeveloped twice). The purification afforded the title compound as awhite solid (39.6 mg, 0.0791 mmol, 68% yield). R_(f)=0.27 (CH₂Cl₂). NMRSpectroscopy: 1H NMR (700 MHz, CDCl₃, 25° C., δ): 8.51 (br. s, 1H), 8.03(d, J=8.17 Hz, 2H), 7.68-7.50 (m, 6H), 6.68 (br. s, 1H), 3.93 (s, 3H),3.92 (s, 3H), 3.81 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 166.7,154.1, 142.3, 135.8, 133.1, 131.8, 131.7, 129.7, 129.6, 129.3, 128.1,122.2, 121.8 (q, J=260.8 Hz), 121.3, 119.5, 116.7, 92.4, 89.5, 54.4,52.9, 52.4. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −56.4 (s). MassSpectrometry: HRMS (ESI-TOF) (m/z): calcd for C₂₅H₂₀F₃N₂O₆ ([M+H]⁺),501.1268, found, 501.1273.

N-(6-(((8R,9S,13S,14S)-13-Methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl)oxy)-2-(trifluoro-methoxy)pyridin-3-yl)acetamide(9x)

A solution ofN-hydroxy-N-(6-(((8R,9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl)oxy)pyridin-3-yl)acetamide (8x) (66.0 mg, 0.157 mmol) and Togni reagent I (62.1 mg, 0.188mmol, 1.20 equiv) in CH₂Cl₂ (1.57 mL, 0.100 M) was stirred at 23° C.under N₂ atmosphere for 20 h. The reaction mixture was purified bypreparative TLC (thickness: 1 mm) using hexanes:EtOAc (3:2 (v/v)) fordevelopment (prep TLC was developed three times). The purificationafforded the title compound as a white foamy solid (54.0 mg, 0.111 mmol,71% yield). R_(f)=0.49 (EtOAc:hexanes 1:1 (v/v)). NMR Spectroscopy: ¹HNMR (700 MHz, CDCl₃, 25° C., δ): 8.62 (d, J=8.61 Hz, 1H), 7.37 (s, 1H),7.27 (d, J=8.37 Hz, 1H), 6.91 (dd, J=8.39, 2.37 Hz, 1H), 6.88 (d, J=2.15Hz, 1H), 6.68 (d, J=9.03 Hz, 1H), 2.92-2.86 (m, 2H), 2.51 (dd, J=18.93,8.60 Hz, 1H), 2.44-2.37 (m, 1H), 2.30 (td, J=11.19, 3.44 Hz, 1H), 2.22(s, 3H), 2.18-2.11 (m, 1H), 2.09-2.04 (m, 1H), 2.04-1.99 (m, 1H), 1.96(dt, J=12.48, 3.01 Hz, 1H), 1.67-1.59 (m, 2H), 1.59-1.42 (m, 4H), 0.92(s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 221.0, 168.6, 156.9,151.7, 143.5, 138.2, 136.5, 134.7, 126.6, 120.8, 120.1 (q, J=261.5 Hz),118.1, 118.0, 108.1, 50.6, 48.1, 44.2, 38.2, 36.0, 31.7, 29.5, 26.5,25.9, 24.6, 21.7, 14.0. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −56.4 (s).Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₂₆H₂₈F₃N₂O₄([M+H]⁺⁾, 489.1996, found, 489.2004.

N-(6-((6R,12aR)-6-(Benzo[d][1,3]dioxol-5-yl)-2-methyl-1,4-dioxo-1,3,4,6,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indol-7(2H)-yl)-2-(trifluoromethoxy)pyridin-3-yl)acetamide(9y)

A solution of N-(6-((6R,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2-methyl-1,4-dioxo-1,3,4,6,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indol-7(2H)-yl)-2-(trifluoromethoxy)pyridin-3-yl)acetamide(8y) (50.0 mg, 0.0927 mmol) in CH₂Cl₂ (8.77 mL) was cooled to 4° C. Asolution of Togni reagent I (39.3 mg, 0.119 mmol, 1.20 equiv) in CH₂Cl₂(0.500 mL) was then added dropwise and the reaction mixture was stirredat 4° C. for 16 h. The reaction mixture was concentrated in vacuo. Theresidue was purified by preparative TLC (thickness: 1 mm) usinghexanes:EtOAc (1:4 (v/v)) for development (prep TLC was developedtwice). The purification afforded the title compound as a white solid(37.3 mg, 0.0614 mmol, 66% yield). R_(f)=0.48 (EtOAc). NMR Spectroscopy:¹H NMR (700 MHz, (CD₃)₂SO, 25° C., δ): 9.99 (s, 1H), 8.53 (d, J=8.53 Hz,1H), 7.80-7.72 (m, 1H), 7.42-7.36 (m, 1H), 7.34 (d, J=8.53 Hz, 1H),7.25-7.19 (m, 2H), 6.59 (s, 1H), 6.51 (d, J=8.03 Hz, 1H), 6.32 (d,J=1.76 Hz, 1H), 6.23 (dd, J=8.03, 1.76 Hz, 1H), 5.83 (s, 2H), 4.55 (dd,J=11.54, 4.77 Hz, 1H), 4.24-4.15 (m, 1H), 3.92 (d, J=17.32 Hz, 1H), 3.65(dd, J=16.19, 4.64 Hz, 1H), 3.12 (dd, J=15.81, 12.30 Hz, 1H), 2.90 (s,3H), 2.18 (s, 3H). ¹³C NMR (175 MHz, (CD₃)₂SO, 25° C., δ): 169.4, 166.9,166.3, 146.7, 146.0, 145.4, 141.7, 136.4, 136.0, 134.9, 134.2, 126.1,123.4, 122.3, 121.3, 120.7, 119.7 (q, J=262.6 Hz), 119.1, 118.4, 110.4,109.9, 107.5, 107.4, 100.9, 54.7, 53.9, 51.4, 32.8, 23.6, 23.2. ¹⁹F NMR(376 MHz, (CD₃)₂SO, 25° C., δ): −56.6 (s). Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₃₀H₂₅F₃N₅O₆ ([M+H]⁺), 608.1751, found,608.1761.

Example 8. Trifluoromethoxylation of Pyrimidine Substrates

To probe the applicability of the trifluoromethoxylation reaction toother heteroarenes, pyrimidines substituted with benzimidazolyl (10a),indolyl (10b), methoxy (10c), phenoxy (10d), or estronyl (10e) groupswere examined (Scheme 8). These substrates were trifluoromethoxylated toafford the corresponding desired products (11a-11e) in good yields.Products 11a-11e are shown in FIG. 3.

N-Hydroxy-N-(2-(2-(thiazol-4-yl)-1H-benzo[d]imidazol-1-yl)pyrimidin-5-yl)acetamide (10a)

Under N₂ atmosphere, 4-(1H-benzo[d]imidazol-2-yl)thiazole (362 mg, 1.80mmol, 1.20 equiv) was dissolved in THF (7.50 mL, 0.240 M) and stirred at0° C. NaH (72.0 mg, 1.80 mmol, 1.20 equiv, 60% dispersion in mineraloil) was added in portionwise. After 30 min, a solution of2-chloro-5-nitropyrimidine (239 mg, 1.50 mmol. 1.00 equiv) in THF (2.50mL, 0.600 M) was added and then the reaction mixture was slowly warmedup to 50° C. for 12 h. The reaction mixture was poured to water (100mL), extracted with EtOAc, washed with brine. The combined organiclayers was dried (MgSO₄), filtered and concentrated in vacuo. Theresidue was purified by chromatography on silica gel, eluting withhexanes:EtOAc (5:1 to 1:1 (v/v)), to afford the title compound as ayellow solid (369 mg, 1.14 mmol, 76% yield). R_(f)=0.33 (hexanes:EtOAc2:1 (v/v)). NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃, 25° C., δ): 9.46(s, 2H), 8.70 (d, J=2.15 Hz, 1H), 8.20 (s, 1H), 8.18-8.13 (m, 1H), 7.89(dd, J=6.45, 2.58 Hz, 1H), 7.48-7.43 (m, 2H). ¹³C NMR (175 MHz, CDCl₃,25° C., δ): 159.0, 154.5, 154.4, 152.7, 147.6, 147.3, 143.0, 139.7,134.1, 125.7, 125.2, 121.1, 120.6, 113.6. Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₁₄H₉N₆O₂S ([M+H]⁺), 325.0502, found,325.0506. Under N₂ atmosphere, a suspension of4-(1-(5-nitropyrimidin-2-yl)-1H-benzo[d] imidazol-2-yl) thiazole (200mg, 0.620 mmol, 1.00 equiv) and 5% Rh/C (7.12 mg, 0.60 mol % Rh) in THF(6.20 mL, 0.100 M) was stirred at 23° C. Hydrazine monohydrate (37.0 mg,0.740 mmol, 1.20 equiv) was added dropwise. The reaction mixture wasstirred at 23° C. for 20 min. NaHCO₃ (62.2 mg, 0.740 mmol, 1.20 equiv)was added, followed by dropwise addition of a solution of acetylchloride (58.1 mg, 0.740 mmol, 1.20 equiv) in THF (6.20 mL, 0.120 M).The reaction mixture was stirred at 23° C. for 30 min and then poured towater (100 mL), extracted with EtOAc. The combined organic layers wasdried (MgSO₄), filtered and concentrated in vacuo. The residue waspurified by chromatography on silica gel, eluting with hexanes:EtOAc(1:1 (v/v)), to afford the title compound as a yellow gum (72 mg, 0.204mmol, 33% yield). R_(f)=0.13 (EtOAc). NMR Spectroscopy: ¹H NMR (700 MHz,(CD₃)₂SO, 25° C., δ): 11.23 (s, 1H), 9.21 (s, 2H), 9.00 (br. s., 1H),8.49 (d, J=1.72 Hz, 1H), 7.81 (dd, J=6.45, 1.72 Hz, 1H), 7.74-7.65 (m,1H), 7.41-7.32 (m, 2H), 2.32 (s, 3H). ¹³C NMR (175 MHz, (CD₃)₂SO, 25°C., δ): 171.5, 154.5, 151.2, 148.0, 146.8, 146.3, 142.3, 135.4, 134.8,124.3, 123.6, 122.0, 119.6, 111.9, 22.1. Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₁₆H₁₃N₆O₂S ([M+H]⁺), 353.0815, found,353.0817.

N-(2-(5-Chloro-1H-indol-1-yl)pyrimidin-5-yl)-N-hydroxyacetamide (10b)

Under N₂ atmosphere, 5-chloro-1H-indole (0.570 g, 3.76 mmol, 1.20 equiv)was dissolved in DMF (10 mL, 0.376 M) and stirred at 0° C. NaH (0.15 g,3.76 mmol, 1.20 equiv, 60% dispersion in mineral oil) was added inportionwise. After 30 min, a solution of 2-chloro-5-nitropyrimidine(0.500 g, 3.13 mmol. 1.00 equiv) in DMF (5.6 mL, 0.559 M) was added andthen the reaction mixture was slowly warmed up to 50° C. for 12 h. Thereaction mixture was poured to a solution of LiCl (100 mL), extractedwith EtOAc. The combined organic layers washed with brine, dried(MgSO₄), filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel, eluting with hexanes:EtOAc (10:1 to 5:1(v/v)), to afford the title compound as a yellow solid (0.710 g, 2.58mmol, 83% yield). R_(f)=0.76 (hexanes:EtOAc 4:1 (v/v)). NMRSpectroscopy: ¹H NMR (700 MHz, CDCl₃, 25° C., δ): 9.43 (s, 2H), 8.69 (d,J=8.60 Hz, 1H), 8.27 (d, J=3.87 Hz, 1H), 7.58 (d, J=1.72 Hz, 1H), 7.33(dd, J=8.82, 1.94 Hz, 1H), 6.73 (d, J=3.01 Hz, 1H). ¹³C NMR (175 MHz,CDCl₃, 25° C., δ): 158.7, 154.8, 138.2, 133.9, 133.3, 129.6, 127.5,125.0, 121.0, 118.1, 109.7. Mass Spectrometry: HRMS (ESI-TOF) (m/z):calcd for C₁₂H₁₁ClN₅O₂ ([M+NH₄]⁺), 292.0596, found, 292.0599. Under N₂atmosphere, a suspension of 5-chloro-1-(5-nitropyrimidin-2-yl)-1H-indole(300 mg, 1.09 mmol, 1.00 equiv) and 5% Rh/C (12.6 mg, 0.60 mol % Rh) inTHF (10.9 mL, 0.100 M) was stirred at 23° C. Hydrazine monohydrate (65.6mg, 1.31 mmol, 1.20 equiv) was added dropwise. The reaction mixture wasstirred at 23° C. for 20 min. NaHCO₃ (110 mg, 1.31 mmol, 1.20 equiv) wasadded, followed by dropwise addition of a solution of acetyl chloride(103 mg, 1.31 mmol, 1.20 equiv) in THF (10.9 mL, 0.120 M). The reactionmixture was stirred at 23° C. for 30 min and then poured to water (100mL), extracted with EtOAc. The combined organic layers was dried(MgSO₄), filtered and concentrated in vacuo. The residue wasrecrystalized from hexanes/EtOAc, to afford the title compound as ayellow solid (205 mg, 0.677 mmol, 62% yield). R_(f)=0.14 (hexanes:EtOAc2:1 (v/v)). ¹H NMR (700 MHz, (CD₃)₂SO, 25° C., δ): 11.10 (s, 1H), 9.13(s, 2H), 8.69 (d, J=9.03 Hz, 1H), 8.30 (d, J=3.87 Hz, 1H), 7.72 (d,J=2.15 Hz, 1H), 7.34 (dd, J=8.60, 2.15 Hz, 1H), 6.78 (d, J=3.87 Hz, 1H),2.28 (s, 3H). ¹³C NMR (175 MHz, (CD₃)₂SO, 25° C., δ): 171.0, 152.5,148.9, 133.1, 133.0, 132.0, 127.3, 126.4, 123.4, 120.2, 117.0, 106.1,21.8. Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₁₄H₁₂ClN₄O₂([M+H]⁺), 303.0643, found, 303.0645.

N-Hydroxy-N-(2-methoxypyrimidin-5-yl)acetamide (10c)

Under N₂ atmosphere, a suspension of 2-methoxy-5-nitropyrimidine (180mg, 1.16 mmol, 1.00 equiv) and 5% Rh/C (13.8 mg, 0.60 mol % Rh) in THF(11.6 mL, 0.100 M) was stirred at 23° C. Hydrazine monohydrate (69.7 mg,1.39 mmol, 1.20 equiv) was added dropwise. The reaction mixture wasstirred at 23° C. for 20 min. NaHCO₃ (117 mg, 1.39 mmol, 1.20 equiv) wasadded, followed by dropwise addition of a solution of acetyl chloride(109 mg, 1.39 mmol, 1.20 equiv) in THF (11.6 mL, 0.120 M). The reactionmixture was stirred at 23° C. for 30 min and then filtered through ashort pad of celite. The celite was washed with EtOAc. The combinedorganic solution was concentrated in vacuo. The residue was purified bychromatography on silica gel, eluting with hexanes:EtOAc (2:1 to 0:1(v/v)), to afford the title compound as a gray gum (125 mg, 0.682 mmol,59% yield). R_(f)=0.33 (EtOAc). NMR Spectroscopy: ¹H NMR (700 MHz,(CD₃)₂SO, 25° C., δ): 10.93 (br. s, 1H), 8.81 (s, 2H), 3.91 (s, 3H),2.22 (br. s., 3H). ¹³C NMR (175 MHz, (CD₃)₂SO, 25° C., δ): 170.7, 161.8,151.0, 131.8, 54.9, 21.6. Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcdfor C₇H₁₀N₃O₃ ([M+H]⁺), 184.0717, found, 184.0718.

N-(2-(4-Chloro-3,5-dimethylphenoxy)pyrimidin-5-yl)-N-hydroxyacetamide(10d)

Under N₂ atmosphere, 4-chloro-3,5-dimethylphenol (240 mg, 1.52 mmol,1.20 equiv) was dissolved in THF (8.40 mL, 0.181 M) and stirred at 0° C.NaH (60.8 mg, 1.52 mmol, 1.20 equiv, 60% dispersion in mineral oil) wasadded in portionwise. After 30 min, a solution of2-chloro-5-nitropyrimidine (200 mg, 1.24 mmol. 1.00 equiv) in THF (4.00mL, 0.310 M) was added and then the reaction mixture was slowly warmedto 50° C. for 12 h. The reaction mixture was poured to water (100 mL),extracted with EtOAc, washed with brine. The combined organic layers wasdried (MgSO₄), filtered and concentrated in vacuo. The residue waspurified by chromatography on silica gel, eluting with hexanes:EtOAc(20:1 to 1:1 (v/v)), to afford the title compound as a yellow solid (288mg, 1.03 mmol, 83% yield). R_(f)=0.61 (hexanes:EtOAc 10:1 (v/v)). NMRSpectroscopy: ¹H NMR (500 MHz, CDCl₃, 25° C., δ): 9.32 (s, 2H), 6.94 (s,2H), 2.41 (s, 6H). ¹³C NMR (125 MHz, CDCl₃, 25° C., δ): 167.1, 156.5,149.9, 139.1, 138.4, 132.7, 121.1, 21.1. Mass Spectrometry: HRMS(ESI-TOF) (m/z): calcd for C₁₂H₁₁ClN₃O₃ ([M+H]⁺), 280.0483, found,280.0483. Under N₂ atmosphere, a suspension of2-(4-chloro-3,5-dimethylphenoxy)-5-nitropyrimidine (140 mg, 0.500 mmol,1.00 equiv) and 5% Rh/C (5.70 mg, 0.60 mol % Rh) in THF (5.00 mL, 0.100M) was stirred at 23° C. Hydrazine monohydrate (30.0 mg, 0.60 mmol, 1.20equiv) was added dropwise. The reaction mixture was stirred at 23° C.for 20 min. NaHCO₃ (50.4 mg, 0.600 mmol, 1.20 equiv) was added, followedby dropwise addition of a solution of acetyl chloride (47.1 mg, 0.600mmol, 1.20 equiv) in THF (5.00 mL, 0.120 M). The reaction mixture wasstirred at 23° C. for 30 min and then poured to water (100 mL),extracted with EtOAc. The combined organic layers was dried (MgSO₄),filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel, eluting with hexanes:EtOAc (1:1 to 0:1(v/v)), to afford the title compound as a yellow solid (49.1 mg, 0.160mmol, 32% yield). R_(f)=0.53 (EtOAc). NMR Spectroscopy: ¹H NMR (700 MHz,(CD₃)₂SO, 25° C., δ): 10.99 (br. s., H), 8.86 (s, 2H), 7.08 (s, 2H),2.33 (s, 6H), 2.23 (br. s., 3H). ¹³C NMR (175 MHz, (CD₃)₂SO, 25° C., δ):170.9, 161.0, 151.0, 137.1, 133.0, 129.9, 121.6, 21.6, 20.3. MassSpectrometry: HRMS (ESI-TOF) (m/z): calcd for C₁₄H₁₅ClN₃O₃ ([M+H]⁺),308.0802, found, 308.0797.

N-Hydroxy-N-(2-(((8R,9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl)oxy)pyrimidin-5-yl)acetamide(10e)

Under N₂ atmosphere, estrone (200 mg, 0.740 mmol, 1.00 equiv) wasdissolved in THF (3.70 mL, 0.200 M) and stirred at 0° C. NaH (29.6 mg,0.740 mmol, 1.00 equiv, 60% dispersion in mineral oil) was added inportionwise. After 30 min, a solution of 2-chloro-5-nitropyrimidine (130mg, 0.81 mmol. 1.10 equiv) in THF (1.30 mL, 0.623 M) was added and thenthe reaction mixture was slowly warmed to 50° C. for 12 h. The reactionmixture was poured to water (100 mL), extracted with EtOAc, washed withbrine. The combined organic layers was dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by chromatography onsilica gel, eluting with hexanes:EtOAc (5:1 to 2:1 (v/v)), to afford thetitle compound as a yellow solid (235 mg, 0.597 mmol, 81% yield).R_(f)=0.33 (hexanes:EtOAc 4:1 (v/v)). NMR Spectroscopy: ¹H NMR (700 MHz,CDCl₃, 25° C., δ): 9.32 (s, 2H), 7.38 (d, J=8.60 Hz, 1H), 6.97 (dd,J=8.60, 2.15 Hz, 1H), 6.92 (d, J=2.15 Hz, 1H), 2.97-2.91 (m, 2H), 2.51(dd, J=19.36, 8.60 Hz, 1H), 2.46-2.40 (m, 1H), 2.34 (td, J=11.08, 4.09Hz, 1H), 2.19-2.11 (m, 1H), 2.10-2.02 (m, 2H), 1.98 (dt, J=12.80, 2.85Hz, 1H), 1.68-1.57 (m, 3H), 1.57-1.46 (m, 3H), 0.92 (s, 3H). ¹³C NMR(175 MHz, CDCl₃, 25° C., δ): 220.8, 167.3, 156.4, 150.2, 138.9, 138.3,127.0, 121.2, 118.5, 50.5, 48.0, 44.3, 38.0, 35.9, 31.6, 29.6, 26.4,25.8, 21.7, 13.9. Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd forC₂₂H₂₄N₃O₄ ([M+H]⁺), 394.1761, found, 394.1758.

Under N₂ atmosphere, a suspension of(8R,9S,13S,14S)-13-methyl-3-((5-nitropyrimidin-2-yl)oxy)-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one(170 mg, 0.430 mmol, 1.00 equiv) and 5% Rh/C (4.90 mg, 0.60 mol % Rh) inTHF (4.30 mL, 0.100 M) was stirred at 23° C. Hydrazine monohydrate (26.0mg, 0.52 mmol, 1.20 equiv) was added dropwise. The reaction mixture wasstirred at 23° C. for 20 min. NaHCO₃ (43.7 mg, 0.520 mmol, 1.20 equiv)was added, followed by dropwise addition of acetyl chloride (40.8 mg,0.520 mmol, 1.20 equiv) in THF (4.30 mL, 0.120 M). The reaction mixturewas stirred at 23° C. for 30 min and then poured to water (100 mL),extracted with EtOAc. The combined organic layers was dried (MgSO₄),filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel, eluting with hexanes:EtOAc (2:1 (v/v)), toafford the title compound as a yellow solid (38 mg, 0.0902 mmol, 21%yield). R_(f)=0.50 (EtOAc). NMR Spectroscopy: ¹H NMR (700 MHz, (CD₃)₂SO,25° C., δ): 10.98 (br. s., 1H), 8.83 (s, 1H), 7.33 (d, J=8.17 Hz, 1H),6.93 (dd, J=8.60, 2.58 Hz, 1H), 6.89 (d, J=2.58 Hz, 1H), 2.88-2.84 (m,2H) 2.45 (dd, J=19.15, 8.39 Hz, 1H), 2.42-2.38 (m, 1H), 2.30-2.25 (m,1H), 2.23 (br. s., 3H), 2.11-2.05 (m, 1H), 2.00-1.93 (m, 2H) 1.80-1.76(m, 1H), 1.62-1.36 (m, 6H), 0.86 (s, 3H). ¹³C NMR (175 MHz, (CD₃)₂SO,δ): 219.7, 170.8, 161.3, 150.8, 138.0, 136.6, 132.8, 126.6, 121.2,118.7, 49.6, 47.3, 43.6, 37.6, 35.4, 31.4, 29.0, 25.9, 25.4, 21.6, 21.2,13.5. Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C₂₄H₂₈N₃O₄([M+H]⁺), 422.2074, found, 422.2074.

N-(2-(2-(Thiazol-4-yl)-1H-benzo[d]imidazol-1-yl)-4-(trifluoromethoxy)pyrimidin-5-yl)acetamide (11a)

A solution of N-hydroxy-N-(2-(2-(thiazol-4-yl)-1H-benzo[d]imidazol-1-yl)pyrimidin-5-yl)acetamide (10a) (52.0 mg, 0.148 mmol) andTogni reagent I (58.8 mg, 0.178 mmol, 1.20 equiv) in CH₂Cl₂ (1.48 mL,0.100 M) was stirred at 23° C. under N₂ atmosphere for 22 h. Thereaction mixture was concentrated in vacuo. The residue was dissolved inMeNO₂ (1.48 mL, 0.100 M) and the reaction mixture was stirred at 80° C.for 18 h. The reaction mixture was concentrated in vacuo. The residuewas purified by preparative TLC (thickness: 1 mm) using hexanes:EtOAc(1:4 (v/v)) for development (prep TLC was developed twice). Thepurification afforded the title compound as an off-white solid (45.9 mg,0.109 mmol, 74% yield). R_(f)=0.59 (EtOAc). NMR Spectroscopy: 1H NMR(700 MHz, CDCl₃, 25° C., δ): 9.70 (s, 1H), 8.66 (d, J=2.15 Hz, 1H), 8.14(d, J=2.15 Hz, 1H), 7.97 (dd, J=6.24, 3.23 Hz, 1H), 7.86-7.82 (m, 1H),7.80 (s, 1H), 7.42-7.36 (m, 2H), 2.23 (s, 3H). ¹³C NMR (175 MHz, CDCl₃,25° C., δ): 168.8, 152.7, 152.1, 151.5, 149.4, 147.3, 147.1, 142.7,134.6, 125.1, 124.4, 120.8, 120.1, 119.6, 119.5 (q, J=265.7 Hz), 112.8,24.4. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −57.0 (s). Mass Spectrometry:HRMS (ESI-TOF) (m/z): calcd for C₁₇H₁₂F₃N₆O₂S ([M+H]⁺), 421.0689, found,421.0693.

N-(2-(5-Chloro-1H-indol-1-yl)-4-(trifluoromethoxy)pyrimidin-5-yl)acetamide(11b)

A solution ofN-(2-(5-chloro-1H-indol-1-yl)pyrimidin-5-yl)-N-hydroxyacetamide (10b)(50.0 mg, 0.165 mmol) and Togni reagent I (65.4 mg, 0.198 mmol, 1.20equiv) in CH₂Cl₂ (16.5 mL, 0.010 M) was stirred at 23° C. under N₂atmosphere for 24 h. The reaction mixture was concentrated in vacuo. Theresidue was purified by preparative TLC (thickness: 1 mm) usinghexanes:EtOAc (3:2 (v/v)) for development (prep TLC was developedtwice). The purification afforded the title compound as an off-whitesolid (42.8 mg, 0.115 mmol, 70% yield). R_(f)=0.61 (EtOAc:hexanes 1:1(v/v)). NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃, 25° C., δ): 9.55 (s,1H), 8.54 (d, J=9.03 Hz, 1H), 8.13 (d, J=3.44 Hz, 1H), 7.56 (d, J=2.15Hz, 1H), 7.28 (dd, J=8.60, 2.15 Hz, 1H), 7.18 (s, 1H), 6.62 (d, J=3.44Hz, 1H), 2.29 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 168.5,152.6, 152.4, 151.1, 133.5, 132.5, 128.2, 127.1, 124.2, 120.6, 120.0 (q,J=265.0 Hz), 116.8, 116.6, 107.0, 24.4. ¹⁹F NMR (376 MHz, CDCl₃, 25° C.,δ): −56.6 (s). Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd forC₁₅H₁₁ClF₃N₄O₂ ([M+H]⁺), 371.0517, found, 371.0523.

N-(2-Methoxy-4-(trifluoromethoxy)pyrimidin-5-yl)acetamide (11c)

A solution of N-hydroxy-N-(2-methoxypyrimidin-5-yl)acetamide (10c) (45.0mg, 0.246 mmol) and Togni reagent I (97.4 mg, 0.295 mmol, 1.20 equiv) inCH₂Cl₂ (2.46 mL, 0.100 M) was stirred at 23° C. under N₂ atmosphere for21 h. The reaction mixture was concentrated in vacuo. The residue waspurified by preparative TLC (thickness: 1 mm) using hexanes:EtOAc (1:1(v/v)) for development (prep TLC was developed twice). The purificationafforded the title compound as a white solid (48.7 mg, 0.194 mmol, 79%yield). R_(f)=0.38 (EtOAc:hexanes 1:1 (v/v)). NMR Spectroscopy: ¹H NMR(700 MHz, CDCl₃, 25° C., δ): 9.22 (s, 1H), 7.46 (br. s, 1H), 3.96 (s,3H), 2.22 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 168.8, 160.4,154.5, 154.3, 119.7 (q, J=264.3 Hz), 115.3, 55.6, 24.0. ¹⁹F NMR (376MHz, CDCl₃, 25° C., δ): −56.6 (s). Mass Spectrometry: HRMS (ESI-TOF)(m/z): calcd for C₈H₉F₃N₃O₃ ([M+H]⁺), 252.0591, found, 252.0593.

N-(2-(4-Chloro-3,5-dimethylphenoxy)-4-(trifluoromethoxy)pyrimidin-5-yl)acetamide(11d)

A solution ofN-(2-(4-chloro-3,5-dimethylphenoxy)pyrimidin-5-yl)-N-hydroxyacetamide(10d) (30.5 mg, 0.0991 mmol) and Togni reagent I (39.3 mg, 0.119 mmol,1.20 equiv) in CH₂Cl₂ (2.97 mL, 0.334 M) was stirred at 23° C. under N₂atmosphere for 24 h. The reaction mixture was then stirred at 50° C. for22 h. The reaction mixture was concentrated in vacuo. The residue waspurified by preparative TLC (thickness: 1 mm) using hexanes:EtOAc (3:2(v/v)) for development (prep TLC was developed once). The purificationafforded the title compound as a white solid (26.5 mg, 0.0705 mmol, 71%yield). R_(f)=0.40 (EtOAc:hexanes 2:3 (v/v)). NMR Spectroscopy: ¹H NMR(400 MHz, CDCl₃, 25° C., δ): 9.32 (s, 1H), 7.16 (br. s, 1H), 6.92 (s,2H), 2.38 (s, 6H), 2.25 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ):168.5, 159.3, 154.2, 153.5, 150.2, 137.8, 131.7, 121.3, 119.8 (q,J=265.1 Hz), 116.7, 24.3, 21.0. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ):−56.7 (s). Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd forC₁₅H₁₄ClF₃N₃O₃ ([M+H]⁺), 376.0670, found, 376.0677.

N-(2-(((8S,9R,13R,14R)-13-Methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl)oxy)-4-(trifluoromethoxy)pyrimidin-5-yl)acetamide(11e)

A solution ofN-hydroxy-N-(2-(((8S,9R,13R,14R)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl)oxy)pyrimidin-5-yl)acetamide(10e) (25.0 mg, 0.0593 mmol) and Togni reagent I (23.5 mg, 0.0712 mmol,1.20 equiv) in CH₂Cl₂ (0.593 mL, 0.100 M) was stirred at 23° C. under N₂atmosphere for 16 h. The reaction mixture was then stirred at 50° C. for24 h. The reaction mixture was concentrated in vacuo. The residue waspurified by preparative TLC (thickness: 1 mm) using hexanes:EtOAc (3:2(v/v)) for development (prep TLC was developed twice). The purificationafforded the title compound as a white solid (14.9 mg, 0.0304 mmol, 51%yield). R_(f)=0.47 (EtOAc:hexanes 3:2 (v/v)). NMR Spectroscopy: ¹H NMR(700 MHz, CDCl₃, 25° C., δ): 9.32 (s, 1H), 7.32 (d, J=8.60 Hz, 1H), 7.14(s, 1H), 6.96 (dd, J=8.39, 2.37 Hz, 1H), 6.92 (d, J=2.58 Hz, 1H),2.95-2.90 (m, 2H), 2.51 (dd, J=18.93, 8.60 Hz, 1H), 2.45-2.39 (m, 1H),2.31 (td, J=11.19, 3.87 Hz, 1H), 2.25 (s, 3H), 2.19-2.11 (m, 1H),2.09-2.05 (m, 1H), 2.04-2.00 (m, 1H), 1.97 (dt, J=12.58, 3.17 Hz, 1H),1.67-1.60 (m, 2H), 1.58 (dd, J=12.48, 3.87 Hz, 1H), 1.56-1.43 (m, 3H),0.92 (s, 3H). ¹³C NMR (175 MHz, CDCl₃, 25° C., δ): 221.0, 168.4, 159.6,154.3, 153.5, 150.5, 138.3, 137.4, 126.7, 121.5, 119.8 (q, J=265.1 Hz),118.7, 116.5, 50.6, 48.1, 44.3, 38.1, 36.0, 31.7, 29.6, 26.5, 25.8,24.3, 21.7, 14.0. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −56.6 (s). MassSpectrometry: HRMS (ESI-TOF) (m/z): calcd for C₂₅H₂₇F₃N₃O₄ ([M+H]⁺),490.1948, found, 490.1957.

Example 9. Gram Scale Reaction of Pyridine Substrates and FurtherFunctionalization

To ensure that the products disclosed herein can serve as usefulbuilding blocks for molecular screening, the protocol must be scalableand further functionalization of the trifluoromethoxylated products mustbe possible. To evaluate the reaction efficacy on preparative scale, agram-scale reaction of 8a (1.39 g, 5.00 mmol) was performed (Scheme 9a)and the efficiency of the small-scale reaction was retained uponscale-up. The trifluoromethoxylated products also proved to be versatile(Scheme 9). For examples, 9a could be further elaborated throughpalladium-catalyzed Suzuki and Sonogashira couplings to afford thedesired products (13a, 15a) in good yields. In addition, deprotectedamino-pyridine (9a′) could be efficiently incorporated into othermolecules through amidation and palladium-catalyzed Buchwald-Hartwigcoupling (12a, 14a).

Methyl (5-bromo-6-methoxy-2-(trifluoromethoxy)pyridin-3-yl) carbamate(9a)

A solution of methyl (5-bromo-6-methoxypyridin-3-yl)(hydroxy)carbamate(8a) (1.39 g, 5.00 mmol) and Togni reagent I (1.98 g, 6.00 mmol, 1.20equiv) in CH₂Cl₂ (50.0 mL, 0.100 M) was stirred at 23° C. under N₂atmosphere for 18 h. The reaction mixture was concentrated in vacuo. Theresidue was purified by flash chromatography eluting with hexanes andthen with EtOAc:hexanes (3:17 (v/v)). The purification afforded thetitle compound (2.51 g, 9.05 mmol, 95% yield), which wasspectroscopically identical to the compound prepared according to thestandard procedure (vide supra).

N-(5-Bromo-6-methoxy-2-(trifluoromethoxy)pyridin-3-yl)-2-(thiophen-2-yl)acetamide(12a)

To a solution of 2-(thiophen-2-yl)acetic acid (49.5 mg, 0.348 mmol, 2.0equiv), DMF (1 drop) and DCM (3.50 mL, 0.100 M) at 0° C. under N₂atmosphere was added dropwise oxalyl chloride (44.2 mg, 0.348 mmol, 2.0equiv) via a syringe. The resulting mixture was stirred at 23° C. for 2h, concentrated to afford crude acid chloride, which was used in thesubsequent step without further purification. The above crude acidchloride was dissolved in CH₃CN (1.5 mL, 0.0232 M) and added to asolution of 5-bromo-6-methoxy-2-(trifluoromethoxy)pyridin-3-amine (9a′)(50 mg, 0.174 mmol, 1.0 equiv) in CH₃CN (3.5 mL, 0.0497 M) at 23° C.under N₂ atmosphere. The reaction mixture was stirred at 23° C. foranother 2 h, concentrated in vacuo and purified by chromatography onsilica gel, eluting with hexanes:EtOAc (5:1 (v/v)), to afford the titlecompound as a yellow solid (69.0 mg, 0.167 mmol, 96% yield). R_(f)=0.20(EtOAc:hexanes 1:4 (v/v)). NMR Spectroscopy: ¹H NMR (500 MHz, CDCl₃, 25°C., δ): 8.87 (s, 1H), 7.40 (br. s., 1H), 7.34 (dd, J=5.04, 1.07 Hz, 1H),7.09-7.03 (m, 2H), 3.97 (s, 2H), 3.92 (s, 3H). ¹³C NMR (125 MHz, CDCl₃,25° C., δ): 168.1, 154.2, 142.2, 136.5, 134.8, 128.3, 127.9, 126.6,119.9 (q, J=261.8 Hz), 116.8, 102.6, 55.2, 38.4. ¹⁹F NMR (376 MHz,CDCl₃, 25° C., δ): −57.1 (s). Mass Spectrometry: HRMS (ESI-TOF) (m/z):calcd for C₁₃H₁₁BrF₃N₂O₃S ([M+H]⁺), 412.9600, found, 412.9605.

tert-Butyl4-(3-(2-methoxy-5-((methoxycarbonyl)amino)-6-(trifluoromethoxy)pyridin-3-yl)benzoyl)piperazine-1-carboxylate(13a)

Methyl (5-bromo-6-methoxy-2-(trifluoromethoxy)pyridin-3-yl)carbamate(9a) (0.0600 g, 0.170 mmol, 1.00 equiv), methyl tert-butyl4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)piperazine-1-carboxylate (0.103 g, 0.240 mmol, 1.40 equiv), Na₂CO₃(0.287 g, 0.430 mmol, 2.5 equiv), THF:H₂O 4:3 (1.01 mL, 0.200 M), andpalladium-tetrakis(triphenylphosphine) (0.002 g, 0.020 mmol, 0.0500equiv) were degassed via three freeze-pump-thaw cycles. The resultingmixture was heated at 60° C. for 72 hours and then allowed to cool toroom temperature after which water was added (twice the volume ofTHF:H₂O 4:3 used). The mixture was then extracted with ethyl acetate(twice the volume of THF:H₂O 4:3 used) and the organic extracts wasdried with MgSO₄, filtered purified by preparative TLC (thickness: 1 mm)using EtOAc:hexanes (2:3 (v/v)) for development (prep TLC was developedthree times) to afford the pure cross-coupled product as a white solid(0.077 g, 0.14 mmol, 79% yield). R_(f)=0.20 (EtOAc:hexanes 2:3 (v/v)).NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃, 25° C., δ): 8.47 (br. s, 1H),7.64-7.59 (m, 2H), 7.47 (t, J=8.17 Hz, 1H), 7.40 (d, J=7.31 Hz, 1H),6.68 (br. s, 1H), 3.90 (s, 3H), 3.80 (s, 3H), 3.76 (br. s., 2H),3.60-3.34 (m, 6H), 1.47 (s, 9H). ¹³C NMR (175 MHz, CDCl₃, ° C., δ):170.4, 154.7, 154.1, 142.5, 135.7, 135.5, 133.4, 130.7, 128.9, 127.9,126.7, 121.0, 120.2 (q, J=261.2 Hz), 116.7, 80.5, 54.4, 52.9, 47.7,43.8, 42.2, 28.5. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −56.4 (s).

Methyl2-((5-bromo-6-methoxy-2-(trifluoromethoxy)pyridin-3-yl)amino)benzoate(14a)

A mixture of 5-bromo-6-methoxy-2-(trifluoromethoxy)pyridin-3-amine (9a′)(50.0 mg, 0.200 mmol, 1.20 equiv), methyl 2-iodobenzoate (44.5 mg, 0.170mmol, 1.00 equiv), xantphos (10.0 mg, 0.0170 mmol, 0.100 equiv),NaO^(t)Bu (2.30 mg, 0.238 mmol, 1.40 equiv), and Pd₂(dba)₃ (7.80 mg,0.00850 mmol, 0.05 equiv) in toluene (0.850 mL, 0.200 M) was stirred at100° C. under N₂ for 40 hours and then allowed to cool to roomtemperature. The reaction was purified by preparative TLC (thickness: 1mm) using EtOAc:hexanes (1:10 (v/v)) for development (prep TLC wasdeveloped two times) to afford title compound as a colorless liquid(61.0 mg, 0.145 mmol, 85% yield). R_(f)=0.71 (EtOAc:hexanes 1:10 (v/v)).NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃, 25° C., δ): 9.23 (s, 1H),8.01-7.97 (m, 1H), 7.95 (s, 1H), 7.36 (t, J=7.74 Hz, 1H), 6.87 (d,J=8.60 Hz, 1H), 6.82-6.79 (m, 1H), 3.99 (s, 3H), 3.92 (s, 3H). ¹³C NMR(125 MHz, CDCl₃, 25° C., δ): 168.9, 154.5, 147.2, 146.8, 139.7, 134.5,131.9, 120.2 (q, J=260.9 Hz), 119.7, 118.3, 113.4, 112.8, 102.1, 52.3,52.1. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −56.5 (s). Mass Spectrometry:HRMS (ESI-TOF) (m/z): calcd for C₁₅H₁₃BrF₃N₂O₄ ([M+H]⁺), 421.0005,found, 421.0010.

Methyl (6-methoxy-5-((4-methoxyphenyl)ethynyl)-2-(trifluoromethoxy)pyridin-3-yl)carbamate (15a)

Under N₂ atmosphere methyl(5-bromo-6-methoxy-2-(trifluoromethoxy)pyridin-3-yl)carbamate (15a)(0.0500 g, 0.140 mmol, 1.00 equiv), l-ethynyl-4-methoxybenzene (0.0270g, 0.200 mmol, 1.40 equiv), copper(I) iodide (0.550 mg, 2.90 μmol,0.0200 equiv), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1.20 mg,1.40 μmol, 0.0200 equiv in THF (0.72 mL, 0.200 M), was heated at 60° C.overnight and then allowed to cool to room temperature after which waterwas added (twice the volume of THF). The mixture was then extracted withethyl acetate (twice the volume of THF:H₂O 4:3 used) and the organicextracts was dried with MgSO₄, filtered purified by preparative TLC(thickness: 1 mm) using EtOAc:hexanes (1:9 (v/v)) for development (prepTLC was developed three times) to afford the pure cross-coupled productas a white solid (0.045 g, 0.11 mmol, 78% yield). R_(f)=0.38(EtOAc:hexanes 3:16 (v/v)). NMR Spectroscopy: ¹H NMR (700 MHz, CDCl₃,25° C., δ): 8.54 (br. s, 1H), 7.50-7.46 (m, 2H), 6.90-6.85 (m, 2H), 6.60(br. s, 1H), 3.96 (s, 3H), 3.83 (s, 3H), 3.81 (s, 3H). ¹³C NMR (175 MHz,CDCl₃, 25° C., δ): 160.0, 157.3, 153.9, 142.1, 135.4, 133.4, 120.3 (q,J=261.6 Hz), 116.1, 115.0, 114.1, 105.3, 95.0, 81.7, 55.5, 54.8, 52.9.¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −56.4 (s).

Example 10. Mechanistic Studies and Proposed Reaction Mechanism

To gain some insight into the reaction mechanism, reactions in thepresence of radical trap butylated hydroxytoluene (BHT) (Scheme 10a)were performed. We chose to use substrate 8d because we could isolatethe O-trifluoromethylated intermediate 8d′ and study each step (i.e.O-trifluoromethylation and OCF₃-migration) separately. Addition of BHT(1 equiv) to a reaction mixture of 8d and Togni reagent I haddetrimental effect to the formation of O-trifluoromethylatedN-hydroxylamine intermediate 8d′. This result suggests the involvementof radical species in the reaction pathway, which is in agreement withliterature precedent.^(4b, 17) On the other hand, BHT did not affect thereaction yield for the OCF₃-migration process (step 2, Scheme 10a).These experiments argue against the presence of long-lived radicalspecies in the OCF₃-migration process and are consistent with ourprevious finding.²⁸ Moreover, introduction of electron rich substituentpara to the N—OCF₃ group facilitates the OCF₃-migration process. Theseobservations support the formation of nitrenium ion andtrifluoromethoxide.^(24,28) On the basis of these results, a plausiblemechanism for the trifluoromethoxylation reaction is illustrated inScheme 10b. Deprotonation of 8d forms N-hydroxyl an ion I, whichundergoes single-electron transfer (SET) with Togni reagent I togenerate N-hydroxyl radical II, trifluoromethyl radical, and alkoxideIII. Recombination of N-hydroxyl radical and trifluoromethyl radicalaffords the O-trifluoromethylated hydroxylamine 1d′, which could beisolated and characterized. This intermediate will then undergothermally induced heterolytic cleavage of the N—O bond to form a tightion pair of nitrenium ion IV and trifluoromethoxide. Recombination ofthis ion pair gives V, which upon tautomerization yields the desiredproduct 9d.

Methyl-(6-bromopyridin-3-yl) (trifluoromethoxy) carbamate (8d′)

A solution of methyl (6-bromopyridin-3-yl)(hydroxy)carbamate (8d) (120.0mg, 0.486 mmol) and Togni reagent I (192.4 mg, 0.583 mmol, 1.20 equiv)in CH₂Cl₂ (4.86 mL, 0.100 M) was stirred at 23° C. under N₂ atmospherefor 19 h. The reaction mixture was concentrated in vacuo. The residuewas purified by preparative TLC (thickness: 1 mm) using hexanes:EtOAc(97:3 (v/v)) for development (prep TLC was developed four times). Theband corresponding to 2-(2-iodophenyl)propan-2-ol was on the bottom ofthe band corresponding to the product, so only top of the bandcorresponding to the product was scraped of the PLC plate. Thepurification afforded the title compound as a white solid (97.4 mg,0.309 mmol, 64% yield). R_(f)=0.49 (EtOAc:hexanes 1:9 (v/v)). NMRSpectroscopy: ¹H NMR (700 MHz, CDCl₃, 25° C., δ): 8.45 (br. s, 1H), 7.60(m, 1H), 7.56 (d, J=8.60 Hz, 1H), 3.90 (s, 3H). ¹³C NMR (175 MHz, CDCl₃,60° C., δ): 155.2, 145.9, 141.2, 137.3, 133.9, 128.5, 122.7 (q, J=263.7Hz), 55.3. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −66.2 (s). MassSpectrometry: HRMS (ESI-TOF) (m/z): calcd for C₈H₇BrF₃N₂O₃ ([M+H]⁺),314.9587, found, 314.9592.

5-Bromo-6-methoxy-2-(trifluoromethoxy)pyridin-3-amine (9a′)

To a stirred suspension of(5-bromo-6-methoxypyridin-3-yl)(hydroxy)carbamate (0.370 g, 1.07 mmol,1.00 equiv) and sodium hydroxide (0.257 g, 6.43 mmol, 6.00 equiv) inEtOH:H₂O 4:3 (6.32 mL, 0.200 M) was heated at 70° C. overnight, cool to−20° C., diluted with water and the crystals formed were filtered off toafford the deprotection of methyl carbamates as pure slightly lightyellow solid (0.263 g, 0.92 mmol, 86% yield). R_(f)=0.69 (EtOAc:hexanes3:7 (v/v)). NMR Spectroscopy: ¹H NMR (500 MHz, (CD₃)₂SO, 25° C., δ):7.55 (s, 1H), 5.17 (s, 2H), 3.77 (s, 3H). ¹³C NMR (175 MHz, (CD₃)₂SO,25° C., δ): 147.73, 137.95, 131.06, 129.42, 120.01 (q, J=257.3 Hz),102.74, 54.17. ¹⁹F NMR (376 MHz, CDCl₃, 25° C., δ): −56.9 (s). MassSpectrometry: HRMS (ESI-TOF) (m/z): calcd for C₇H₇BrF₃N₂O₂ ([M+H]⁺),288.9618, found, 288.9629.

O-Trifluoromethylation in the Presence of a Radical Trap

A solution of methyl (6-bromopyridin-3-yl)(hydroxy)carbamate (8d) (12.4mg, 0.0502 mmol, 1.00 equiv), BHT (11.0 mg, 0.0500 mmol, 1.00 equiv) andTogni reagent I (19.8 mg, 0.0600 mmol, 1.2 equiv) in CH₂Cl₂ (0.500 mL)was stirred at 23° C. under N₂ atmosphere for 21 h. Trifluorotoluene(6.14 μL) and CDCl₃ (0.250 mL) were added and the reaction mixture wasanalyzed by ¹⁹F NMR. The ¹⁹F NMR analysis indicated that the yield ofO-trifluoromethylation of 8d in the presence of BHT (26%) was much lowerthan in the absence of the radical trap (83%).

O—CF₃ Migration in the Presence of a Radical Trap w/o BHT

with BHT:

Reaction without BHT:

Under N₂ atmosphere, a solution of methyl (6-bromopyridin-3-yl)(trifluoromethoxy)carbamate (9.45 mg, 30.0 μmol) (8d′) in MeNO₂ (0.300mL, 0.100 M) was heated at 120° C. for 21 h. Trifluorotoluene (3.68 μL)and CDCl₃ (0.400 mL) were added and the reaction mixture was analyzed by¹⁹F NMR. The ¹⁹F NMR analysis indicated that the yield of OCF₃-migrationreaction was 94% (2.4:1).

Reaction with BHT:

Under N₂ atmosphere, a solution of methyl (6-bromopyridin-3-yl)(trifluoromethoxy)carbamate (8d′) (9.45 mg, 30.0 μmol, 1.00 equiv) andBHT (11.0 mg, 50.0 μmol, 1.00 equiv) in MeNO₂ (0.300 mL, 0.100 M) washeated at 120° C. for 21 h. Trifluorotoluene (3.68 μL) and CDCl₃ (0.400mL) were added and the reaction mixture was analyzed by ¹⁹F NMR. The ¹⁹FNMR analysis indicated that the yield of OCF₃-migration reaction was 90%(2.5:1).

Example 11. Additional Substrates

An additional aspect of the invention provides substituted orunsubstituted aryl and heteroaryl analogs of the compounds of Scheme 2and Schemes 7-8 that readily undergo the two-steptrifluoromethylation-migration sequence or the one-pottrifluoromethylation-migration reaction.

DISCUSSION

Clearly, direct trifluoromethoxylation reactions that avoid use ofhighly toxic and thermally labile reagents are greatly desired.Therefore, we initiated a program to develop easily-handled and benchstable trifluoromethoxylation reagents for direct introduction of theOCF₃ group into various organic molecules to facilitate studies of thisfunctional group in the context of material, agricultural, andpharmaceutical regimes. In the course of the trifluoromethoxylationreagent development, we observed a thermally induced OCF₃-migration togenerate synthetically useful ortho-trifluoromethoxylated anilinederivatives (Scheme 1).^([13]) Herein, we report the first synthesis,isolation, and characterization of protectedN-aryl-N-(trifluoro-methoxy)amines^([14]) and their application in thesynthesis of ortho-OCF₃ aniline derivatives.

A proposed mechanistic pathway for OCF₃-migration is depicted in Scheme6A. The thermally induced heterolytic cleavage of the N—O bond of 2liberates an ion pair of a nitrenium ion and trifluoromethoxide (I).Recombination of this ion pair affords intermediate II, which thentautomerizes to restore the aromaticity and generate the desired product3. The proposed mechanism is supported by the following observations.First of all, comparable yields were obtained regardless of the presenceor absence of the radical trap (BHT) in the reaction mixture (Scheme11B). This indicates that formation of long-lived radical species underthe reaction conditions is unlikely. Secondly, we isolated benzoxazole4r from the rearrangement reaction of 2r (Scheme 11C). Presumably, thisside product can result from the competing reaction pathway a once thenitrenium ion III is generated. Finally, Kikugawa and coworkers reportedan AlCl₃-mediated regioselective OCH₃-migration ofN-methoxy-N-phenylamides to produce ortho-OCH₃ anilinederivatives.^([3]) A reaction mechanism involving a heterolytic cleavageof the N—O bond to furnish an ion pair was proposed (Scheme 11D).

[a] 1 equiv of BHT was used.

The first O-trifluoromethylation of a wide range of protectedN-aryl-N-hydroxylamines and the first OCF₃-migration reaction to affordvarious ortho-OCF₃ aniline derivatives, which can be useful synthons foragrochemical and pharmaceutical development, as beendeveloped.^([2a,b,5g,22]) The OCF₃-migration reaction proceeds throughthe heterolytic cleavage of the N—O bond followed by recombination ofthe resulting ion pair. The arene trifluoromethoxylation protocolutilizes bench stable reagents, is amenable to gram-scale and one-potsynthesis, and displays high levels of ortho-selectivity as well asfunctional group tolerance.

Also, the first mild, general, and scalable protocol for theregioselective synthesis of trifluoromethoxylated pyridines andpyrimidines was been established. Several unique features distinguishour strategy from the existing approaches: (i) many substrates withcomplex skeleton could be trifluoromethoxylated at or below roomtemperature; (ii) a wide range of functional groups and substitutionpatterns are tolerated; (iii) this transformation could be amenable togram-scale synthesis; (iv) the halogen or amino group could be used assynthetic handles for further elaborations, and (v) the operationalsimplicity of our protocol would render trifluoromethoxylation availableto broader synthetic community. Since heteroarenes are ubiquitous inbiologically active natural products, pharmaceuticals, andagrochemicals, OCF₃-containing heteroarenes will be invaluable for thediscovery and development of new drugs, agrochemicals, and functionalmaterials. Our current efforts are directed toward development ofintermolecular trifluoromethoxylation of hydrocarbons.

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1-9. (canceled)
 10. A process of producing a trifluoromethoxylated arylor trifluoromethoxylated heteroaryl having the structure:

wherein A is an aryl or heteroaryl, each with or without subsutitution;and R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl),(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂, —NH-(alkenyl),—NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl), —O-(alkenyl),—O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl),—S-(alkynyl), —S-(aryl), or —S-(heteroaryl). comprising: (b) maintainingthe compound having the structure:

in a second suitable solvent under conditions sufficient to produce thetrifluoromethoxylated aryl or trifluormethoxylated heteroaryl having thestructure:


11. The process of claim 10, wherein the second suitable solvent ischloroform, dichloromethane, nitromethane, dimethylforamide, diethylether, tetrahydrofuran, dioxane, dichloroethane, or hexane.
 12. Theprocess of claim 10, wherein step (b) is carried out at roomtemperature.
 13. The process of claim 10, wherein step (b) is carriedout at a temperature of 50-140° C.
 14. The process of claim 10, whereinthe compound is maintained in the second suitable solvent for 10-50hours.
 15. The process of claim 10, wherein A is a phenyl or pyridine.16. The process of claim 10, wherein A is a furan, thiophene, pyrrole,thiazole, imidazole, pyrazole, isooxazole, isothiazole, naphthalene,anthracene, pyrimidine, pyrazine, pyridazine, indole, indoline,benzofuran, benzothiophene, or quinolone.
 17. The process of claim 10,wherein, the compound produced has the structure:

wherein R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl),-(heteroaryl), (alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl); and R₂, R₃,R₄ and R₅ is each independently —H, halogen, —CN, —CF₃, —OCF₃, -(alkyl),-(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH₂, —NH-(alkyl),—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —CO₂-(alkyl),—CO₂-(alkenyl), —CO₂-(alkynyl)-CO₂-(aryl), —C(—CO₂-(heteroaryl),—C(O)NH-(alkyl), —C(O)NH-(alkenyl), —C(O)NH-(alkynyl) —C(O)NH-(aryl),—C(O)NH-(heteroaryl), —C(O)N(alkyl)₂, —OH, —OAc, —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), pyridine, furan,thiophene, pyrrole, thiazole, imidazole, pyrazole, isooxazole,isothiazole, naphthalene, anthracene, pyrimidine, pyrazine, pyridazine,indole, indoline, benzofuran, benzothiophene, or quinolone.
 18. Theprocess of claim 10, wherein the compound produced has the structure:

wherein R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl),-(heteroaryl), (alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl); and R₂, R₃,R₄ and R₅ is each independently —H, halogen, —CN, —CF₃, —OCF₃, -(alkyl),-(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH₂, —NH-(alkyl),—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —CO₂-(alkyl),—CO₂-(alkenyl), —CO₂-(alkynyl)-CO₂-(aryl), —C(—CO₂-(heteroaryl),—C(O)NH-(alkyl), —C(O)NH-(alkenyl), —C(O)NH-(alkynyl) —C(O)NH-(aryl),—C(O)NH-(heteroaryl), —C(O)N(alkyl)₂, —OH, —OAc, —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), -pyridine,furan, thiophene, pyrrole, thiazole, imidazole, pyrazole, isooxazole,isothiazole, naphthalene, anthracene, pyrimidine, pyrazine, pyridazine,indole, indoline, benzofuran, benzothiophene, or quinolone.
 19. Theprocess of claim 10, wherein the compound produced has the structure:

wherein R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl),-(heteroaryl), (alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl); and R₂, R₃and R₅ is each independently —H, halogen, —CN, —CF₃, —OCF₃, -(alkyl),-(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH₂, —NH-(alkyl),—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —CO₂-(alkyl),—CO₂-(alkenyl), —CO₂-(alkynyl)-CO₂-(aryl), —C(—CO₂-(heteroaryl),—C(O)NH-(alkyl), —C(O)NH-(alkenyl), —C(O)NH-(alkynyl) —C(O)NH-(aryl),—C(O)NH-(heteroaryl), —C(O)N(alkyl)₂, —OH, —OAc, —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), pyridine, furan,thiophene, pyrrole, thiazole, imidazole, pyrazole, isooxazole,isothiazole, naphthalene, anthracene, pyrimidine, pyrazine, pyridazine,indole, indoline, benzofuran, benzothiophene, or quinolone; or thestructure:

wherein R₁ is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl),-(heteroaryl), (alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl)₂,—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl); and R₃, R₄and R₅ is each independently —H, halogen, —CN, —CF₃, —OCF₃, -(alkyl),-(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH₂, —NH-(alkyl),—NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —CO₂-(alkyl),—CO₂-(alkenyl), —CO₂-(alkynyl)-CO₂-(aryl), —C(—CO₂-(heteroaryl),—C(O)NH-(alkyl), —C(O)NH-(alkenyl), —C(O)NH-(alkynyl) —C(O)NH-(aryl),—C(O)NH-(heteroaryl), —C(O)N(alkyl)₂, —OH, —OAc, —O-(alkyl),—O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl),—S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), pyridine, furan,thiophene, pyrrole, thiazole, imidazole, pyrazole, isooxazole,isothiazole, naphthalene, anthracene, pyrimidine, pyrazine, pyridazine,indole, indoline, benzofuran, benzothiophene, quinolone, pyrazoline,triazole, benzimidazole, benzotriazole, azaindole, or purine. 20-37.(canceled)